WO2012067663A1

WO2012067663A1 - Compounds

Info

Publication number: WO2012067663A1
Application number: PCT/US2011/024824
Authority: WO
Inventors: Brian Alvin Johns; John Brad Shotwell; David Haigh
Original assignee: Glaxo Group Limited
Priority date: 2010-11-18
Filing date: 2011-02-15
Publication date: 2012-05-24
Also published as: AU2011329485A1; TW201221131A

Abstract

The present invention features compounds of formula (I): and salts thereof, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections.

Description

COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to novel compounds useful as anti-viral agents, specifically Hepatitis C Virus (HCV) inhibitors, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end- stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K.L. (1997) Hepatology 26 (suppl 1 ): 71 S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of those treated, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon, both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359-

362), hepatitis C virus (HCV) is now widely accepted as the most common causative agent of post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). HCV is an enveloped virus containing a single strand RNA molecule of positive polarity.

Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2^nd Edition, p931 -960; Raven Press, N.Y.).

The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al. (2000) Journal of Virology, 74(4), p.2046- 2051 ). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to cure HCV infection.

Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit replication of both genotype 1 a and genotype 1 b of HCV.

SUMMARY OF THE INVENTION

The present invention provides benzofuran compounds substituted at the 6-position with a boron containing moiety, pharmaceutical compositions comprising said compounds, methods of synthesis and uses of such compounds in treating and/or preventing viral infections, such as flavivirus infections, for example, HCV infections.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula (I):

(I)

wherein:

R¹ is one or more substituents independently selected from the group consisting of halogen, Ci_-6alkyl, alkoxy, -CN, -CF₃ and OR¹⁰ wherein R¹⁰ is aryl optionally substituted with halogen; R² is hydrogen, hydroxy, C_1-6alkyl or C_3-6cycloalkyl wherein C_1-6alkyl or C_3-6cycloalkyl may be optionally substituted with hydroxy;

R³ is C_1-6alkyl, C_3-6cycloalkyl or C_1-6alkoxy;

R⁴ is -S(0)₂R⁵, -C(0)OR⁵, or -C(0)NR⁶R⁷ _÷

R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

R⁶ is hydrogen;

R⁷ is hydrogen or Ci_-6alkyl;

X is Ci_-6alkylene optionally substituted with Ci_-6alkyl, hydroxy, amino or C_3-6cycloalkyl; R⁸ is

(a) Het optionally substituted with one or more substituents selected from the group consisting of Ci_-6alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF₃ and - OCF₃;

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^b);

R^a and R^b are hydrogen or Ci_-6alkyl or when Ci_-6alkyl, R^a and R^b together with the oxygen atom to which they are attached form a 5 to 8-membered ring;

R⁹ is alkylene optionally substituted by Ci_-6alkyl;

or a pharmaceutically acceptable salt thereof.

The term "alkyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C_1-6alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 , 1-dimethylpropyl. However, when a moiety is defined such that alkyl bears a substituent it will be clear to the skilled person from the context that alkyl may include alkylene, for example methylene (CH₂), ethylene (CH₂CH₂) and propylene (CH₂CH₂CH₂).

The term "alkylene" refers to a straight or branched chain saturated hydrocarbon linker groups. Examples of alkylene groups include methylene (CH₂), ethylene (CH₂CH₂) and propylene (CH₂CH₂CH₂).

The term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci_-6alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 6, carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, prop-1 -oxy, prop-2-oxy, but-1 - oxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.

The term "halogen" or "halo" refers to a fluorine (fluoro, F), chlorine (chloro, CI), bromine (bromo, Br) or iodine (iodo, I) atom.

The term "hydroxy" refers to a radical or substituent of the formula OH. The term "cycloalkyl" refers to a saturated cyclic group containing 3 to 6 carbon ring- atoms (unless otherwise specified). Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "Het" refers to a 3- to 7-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused. Each Het consists of one or more carbon atoms and either one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms. The Het may be attached at any carbon or N atom, provided that the attachment results in the creation of a stable structure. When the Het has substituents, it is understood that the substituents may be attached to any atom in the ring, provided that a stable chemical structure results. Preferred Het are oxaborolanyl, benzoxaborolyl, and dihyrobenzoxaborolyl.

The present invention features a compound of formula (I) wherein:

R¹ is one or more substituents independently selected from the group consisting of halogen, Ci_-6alkyl, alkoxy, -CN, and -CF₃;

R² is hydrogen, hydroxy, Ci_-6alkyl or C_3-6cycloalkyl wherein Ci_-6alkyl or C₃-₆cycloalkyl may be optionally substituted with hydroxy;

R³ is C_1-6alkyl, C_3-6cycloalkyl or C_1-6alkoxy;

R⁴ is -S(0)₂R⁵, -C(0)OR⁵, or -C(0)NR⁶R⁷ _;

R⁵ is C_1-6alkyl or C_3-6cycloalkyl;

R⁶ is hydrogen;

R⁷ is hydrogen or Ci_-6alkyl;

(a) Het optionally substituted with one or more substituents selected from the group consisting of Ci_-6alkyl and hydroxy;

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^b);

R^a and R^b are hydrogen;

R⁹ is alkylene optionally substituted by Ci_-6alkyl;

or a pharmaceutically acceptable salt thereof.

The present invention also features a compound of formula (I) wherein:

R¹ is one or more substituents independently selected from the group consisting of halogen, -CF₃ and -OR¹⁰ wherein R¹⁰ is aryl optionally substituted with halogen;

R² is C_1-6alkyl optionally substituted with hydroxy;

R³ is C_3-6cycloalkyl; R⁴ is -S(0)₂R⁵

R⁵ is C_1-6alkyl;

X is C_1-6alkylene optionally substituted with C_1-6alkyl;

R⁸ is

(a) Het optionally substituted with one or more substituents selected from the group consisting of Ci_-6alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF₃ and - OCF₃; or

(b) OR⁹B(OR^a)(OR^b);

R^a and R^b are hydrogen;

R⁹ is alkylene optionally substituted by Ci_-6alkyl;

or a pharmaceutically acceptable salt thereof.

The pre la (la)

wherein:

R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy;

R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^b);

R⁹ is alkylene optionally substituted by Ci_-6alkyl;

or a pharmaceutically acceptable salt thereof.

The present invention features a compound of formula (la) wherein:

R³ is C_1-6alkyl, C_3-6cycloalkyl or C_1-6alkoxy;

R⁵ is C_1-6alkyl or C_3-6cycloalkyl;

X is C_1-6alkylene optionally substituted with C_1-6alkyl, hydroxy, amino or C_3-6cycloalkyl; (a) Het optionally substituted with one or more substituents selected from the group consisting of C_1-6alkyl and hydroxy;

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^b);

R^a and R^b are hydrogen;

R⁹ is alkylene optionally substituted by Ci_-6alkyl;

or a pharmaceutically acceptable salt thereof.

The present invention features a compound of formula (I), according to any of the descriptions above, wherein R¹ is one or two substituents selected from halogen.

The present invention features a compound of formula (I), according to any of the descriptions above, wherein R² is Ci_-6alkyl.

The present invention features a compound of formula (I) or (la), according to any of the descriptions above, wherein R³ is C₃-₆cycloalkyl.

The present invention features a compound of formula (I), according to any of the descriptions above, wherein R⁴ is -S(0)₂R⁵ .

The present invention features a compound of formula (I) or (la), according to any of the descriptions above, wherein R⁸ is Het optionally substituted with one or more substituents selected from the group consisting of C_1-6alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF₃ and -OCF₃;

The present invention features a compound of formula (I) or (la), according to any of the descriptions above, wherein R⁸ is Het optionally substituted with one or more substituents selected from the group consisting of Ci_-6alkyl and hydroxyl.

The present invention features a compound of formula (I) or (la), according to any of the descriptions above, wherein R⁸ is OR⁹B(OR^a)(OR^b).

The present invention features a compound of formula (I) or (la), according to any of the descriptions above, wherein R⁸ is N(R⁵)R⁹B(OR^a)(OR^b).

The present invention features a compound of formula (I) or (la), according to any of the descriptions above, wherein X is alkylene.

The present invention also features a compound selected from the group consisting of:

[({2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1- benzofuran-6-yl}(methylsulfonyl)amino]ethyl}oxy)methyl]boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-6- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide; 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

2-(4-Fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-4- yl)methyl](methylsulfonyl)amino]-N-methyl-5-[(1-methylethyl)oxy]-1-benzofuran-3- carboxamide;

2-(4-Fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-N-methyl-5-[(1-methylethyl)oxy]-1-benzofuran-3- carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

(+)-5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

(-)-5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

[({3-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]propyl}oxy)methyl]boronic acid;

[3-({2-[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]ethyl}oxy)propyl]boronic acid;

[({2-[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]ethyl}oxy)methyl]boronic acid;

{3-[{2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1 - benzofuran-6-yl}(methylsulfonyl)amino]ethyl}(methyl)amino]propyl}boronic acid;

5-ethyl-2-(4-Fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

2-(4-Fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]- /V-methyl-5-(1-methylethyl)-1-benzofuran-3-carboxamide;

2-(4-Fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]- /V,5-dimethyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborinan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hydroxy-1 ,2-oxaborolan-4- yl)ethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborinan-5-yl)methyl]

(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[2-(2-hydroxy-1 ,2-oxaborolan-5- yl)ethyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide; [({(2R)-3-[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]-2-methylpropyl}oxy)methyl]boronic acid;

[({(2S)-3-[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]-2-methylpropyl}oxy)methyl]boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)ethylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-2,5-dihydro-1 ,2-oxaborol-4- yl)methyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)propan-2-ylsulfonamido)-N-methylbenzofuran-3-carboxamide;

N,5-Dicyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide;

5-Cyclopropyl-6-(N-((2-hydroxy-1 ,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N- methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide;

2-(4-Chlorophenyl)-5-cyclopropyl-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(3-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(3-fluorophenyl)-6-(N-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-

5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

2-(4-Chlorophenyl)-5-cyclopropyl-6-(/\/-((1 -hydroxy-1 , 3-dihydrobenzo[c][i,2]oxaborol- 5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(3,4-difluorophenyl)-6-(N-((1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide;

5-Cyclopropyl-6-(N-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3- carboxamide;

5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide; (±)-5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-3-methyl-1 ,3-dihydro-2, 1- benzoxaborol-5-yl)methyl](methylsulfonyl)amino]-/V-methyl-1-benzofuran-3-carboxamide;

5-Cyclopropyl-6-(N-((7-fluoro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam

5-Cyclopropyl-6-(N-((4-fluoro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[(3S)-1 -hydroxy-3-methyl-1 ,3-dihydro-2, 1- benzoxaborol-5-yl]methyl}(methylsulfonyl)amino]-/V-methyl-1-benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[(3R)-1-hydroxy-3-methyl-1 ,3-dihydro-2,1 - benzoxaborol-5-yl]methyl}(methylsulfonyl)amino]-/V-methyl-1-benzofuran-3-carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(1 -(1 -hydroxy-1 , 3-dihydrobenzo[c][7,2]oxaborol-

5- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-6-(/V-((6-fluoro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1 -hydroxy-1 , 3- dihydrobenzo[c][i,2]oxaborol-5-yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3- carboxamide;

Methyl 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-

6- yl}(methylsulfonyl)amino]methyl}-1 -hydroxy-1 , 3-dihydro-2,1 -benzoxaborole-7-carboxylate;

5- Cyclopropyl-2-(4-fluorophenyl)-6-[{[1 -hydroxy-7-(hydroxymethyl)-1 ,3-dihydro-2, 1- benzoxaborol-5-yl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide;

6- (/V-((7-Chloro-1-hydroxy-1 ,3-dihydrobenzo[c][i,2]oxaborol-5- yl)methyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/V-methylbenzofuran-3- carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-3,4-dihydro-1 H-2, 1-benzoxaborin-6- yl)methyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-/V-ethyl-6-[[(7-fluoro-1 -hydroxy-1 ,3-dihydro-2, 1 -benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-3-yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3- carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-((1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol- 3-yl)methyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide; 5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-((1-hydroxy-7-(trifluoromethyl)-1 ,3- dihydrobenzo[c][i,2]oxaborol-5-yl)methyl)methylsulfonamido)-/\/-methylbenzofuran-3- carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3S)-1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol- 3-yl]ethyl}(methylsulfonyl)amino]-/\/-methyl-1-benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3R)-1-hydroxy-1 ,3-dihydro-2, 1 -benzoxaborol- 3-yl]ethyl}(methylsulfonyl)amino]-/\/-methyl-1-benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[({1-hydroxy-7-[(trifluoromethyl)oxy]-1 ,3-dihydro- 2 -benzoxaborol-5-yl}methyl)(methylsulfonyl)amino]-/V-methyl-1-benzofuran-3-carboxamide;

6-(N-(2-(7-Chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide;

5- Cyclopropyl-6-[[(7-fluoro-1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide;

5-Cyclopropyl-6-(/V-(2-(7-fluoro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

6- [[2-(6-Chloro-1-hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-3- yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-1 -benzofuran-3- carboxamide;

6-[[2-(5-Chloro-1-hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-3- yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-1 -benzofuran-3- carboxamide;

6-[[2-(4-Chloro-1-hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-3- yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-1 -benzofuran-3- carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1-hydroxy-3,4-dihydro-1 H- benzo[c][1 ,2]oxaborinin-3-yl)ethyl)methylsulfonamido)-/V-methylbenzofuran-3-carboxamide^

5-Cyclopropyl-6-(N-(2-(4-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-6-(N-(2-(5-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-6-(N-(2-(6-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[(4R)-2-hydroxy-1 ,2-oxaborolan-4- yl]methyl}(methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide; and

pharmaceutically acceptable salts thereof.

The present invention also feature a compound selected from the group consisting of: 5- cyclopropyl-6-(N-((7-fluoro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam

6- (/V-((7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][i,2]oxaborol-5- yl)methyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluoropheny^

carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3S)-1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol- 3-yl]ethyl}(methylsulfonyl)amino]-/V-methyl-1-benzofuran-3-carboxamide;

5-cyclopropyl-6-(N-(2-(6-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorop and pharmaceutically acceptable salts thereof.

The present invention features a compound selected from the group consisting of:

5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hydroxy-1 ,2-oxaborolan-4- yl)ethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide; and

pharmaceutically acceptable salts thereof.

The present invention features a compound of formula (I) that is [({2-[{5-cyclopropyl- 2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino] ethyl}oxy)methyl]boronic acid or a pharmaceutically acceptable salt thereof,

Certain compounds of formula (I) and (la) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers

(enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention also extends to conformational isomers of compounds of formula (I) and (la) and any geometric (c/^'s and/or trans) isomers of said compounds.

Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.

Diastereoisomeric mixtures of compounds of formula (I) and (la) may be separated according to methods well known in the literature, for example by preparative HPLC or by chromatographic purifications. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral

intermediate compounds may be resolved and used to prepare chiral compounds of the invention. It is understood that compounds of formula (I) and (la) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

It will also be appreciated that compounds of the invention which exist as polymorphs, and mixtures thereof, are within the scope of the present invention.

The present invention also features a compound of formula (I) or (la) or a

pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use. The term

"pharmaceutically acceptable" when used in relation to an ingredient which may be included in a pharmaceutical composition for administration to a patient, refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical composition and not being deleterious to the recipient thereof.

Salts of compounds of formula (I) or (la) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) or (la) and their pharmaceutically acceptable salts. It will be appreciated that for use in medicine the salts of formula (I) or (la) should be physiologically (i.e. pharmaceutically) acceptable.

The compounds of the present invention may be in the form of their free base or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters thereof.

Also included in the present invention are pharmaceutically acceptable salt complexes. The present invention also covers the pharmaceutically acceptable salts of the compounds of formula (I) and (la). As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Therefore, according to a further aspect, the invention provides a pharmaceutically acceptable salt of a compound of formula (I) or (la) and embodiments thereof.

In certain embodiments, compounds of formula (I ) and (la) may contain an acidic functional group and may therefore be capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. A pharmaceutically acceptable base addition salt may be formed by reaction of a compound of formula (I) or (la) with a suitable strong base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which may be isolated for example by crystallisation and filtration.

Pharmaceutically acceptable base salts include ammonium salts (for example ammonium or tetraalkylammonium), metal salts, for example alkali-metal or alkaline-earth-metal salts (such as hydroxides, sodium, potassium, calcium or magnesium), organic amines (such as tris [also known as tromethamine or tris(hydroxymethyl)aminomethane], ethanolamine, diethylamine, triethanolamine, choline, isopropylamine, dicyclohexylamine or N-methyl-D- glucamine), cationic amino acids (such as arginine, lysine or histidine) or bases for insoluble salts (such as procaine or benzathine).

In certain embodiments, compounds according to formula (I) or (la) may contain a basic functional group and may therefore be capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. A pharmaceutically acceptable acid addition salt may be formed by reaction of a compound of formula (I) or (la) with a suitable strong inorganic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric or perchloric) or a suitable strong organic acid, for example, sulfonic acids [such as p- toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, naphthalenesulfonic (e.g. 2-naphthalenesulfonic)], carboxylic acids (such as acetic, propionic, fumaric, maleic, benzoic, salicylic or succinic), anionic amino acids (such as glutamaic or aspartic), hydroxyl acids (such as citric, lactic, tartaric or glycolic), fatty acids (such as caproic, caprylic, decanoic, oleic or stearic) or acids for insoluble salts (such as pamoic or resinic [e.g. polystyrene sulfonate]), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. In one embodiment, a pharmaceutically acceptable acid addition salt of a compound of formula (I) or (la) is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.

It will be appreciated by those skilled in the art that organoboronic acids and/or their organoboronate esters may form "ate" complex addition salts, such as organoborate complex addition salts, in the presence of suitable nucleophilic complexing reagents. Suitable nucleophilic complexing reagents include, but are not limited to alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, or fluoride. Examples of organoborate complex addition salts and methods for their preparation will be readily apparent. For example, one such suitable organoborate complex addition salt is an alkali metal trihydroxyorganoborate salt, such as a sodium trihydroxyorganoborate salt. By way of illustration, sodium trihydroxyarylborate and sodium trihydroxyalkylborate complex addition salts and methods for their preparation are described in Cammidge, A.N. et al, Org. Lett., 2006, 8, 4071-4074. Pharmaceutically acceptable "ate" complex addition salts as described herein are also considered to be within the scope of this invention.

The present invention features suitable pharmaceutically acceptable salts of the compounds of formula (I) or (la) including acid salts, for example sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and tris (tromethamine - tris(hydroxymethyl)aminomethane) salts and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.

The present invention features pharmaceutically acceptable base addition salts of a compound of formula (I) or (la) which are salts of a strong base, for example, sodium, lysine, ammonium, N-methyl-D-glucamine, potassium, choline, arginine (for example L-arginine) or magnesium. In a further aspect the salt is sodium, lysine, ammonium, N-methyl-D- glucamine, potassium, choline or arginine (for example L-arginine).

Other non-pharmaceutically acceptable salts, for example oxalates, may be used, for example in the isolation of compounds of formula (I) and (la) and are included within the scope of this invention.

The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of formula (I) and (la).

The salts of a compound of formula (I) and (la) may be prepared by contacting appropriate stoichiometric amounts of the free acid with the appropriate base in a suitable solvent. The free acid of a compound of formula (I) or (la) may for example be in solution with the appropriate base added as a solid or both the free acid of a compound of formula (I) or (la) and the appropriate acid may independently be in solution.

Suitable solvents for solubilising a compound of formula (I) or (la) free acid include for example alcohols such as isopropanol; ketones such as acetone; acetonitrile or toluene. If the base is to be added as a solution in a solvent, the solvent used may include acetone, methanol or water.

The salts of a compound of formula (I) or (la) may be isolated in solid form by conventional means from a solution thereof obtained as above. For example, a noncrystalline salt may be prepared by precipitation from solution, spray drying or freeze drying of solutions, evaporating a solution to a glass, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid.

The salts of a compound of formula (I) and (la) may be prepared by directly crystallising from a solvent in which the salt has limited solubility, or by triturating or otherwise crystallising a non-crystalline salt. For example, organic solvents such as acetone, acetonitrile, butanone, 1 -butanol, ethanol, 1 -propanol or tetrahydrofuran or mixtures of such solvents may be used. An improved yield of the salts may be obtained by the evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, for example in stages. Careful control of the precipitation temperature and seeding may be used to improve the reproducibility of the production process and the particle size distribution and form of the product.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compounds of formula (I) and (la) and solvates of the salts of the compounds of formula (I) and (la) are included within the scope of the present invention.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or (la) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Most preferably the solvent used is water and the solvate may also be referred to as a hydrate.

Solvates of compounds of formula (I) and (la) which are suitable for use in medicine are those wherein the solvent is pharmaceutically acceptable. However, solvates having non- pharmaceutically acceptable solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and (la) and their pharmaceutically acceptable salts and solvates.

Furthermore, some of the crystalline forms of the compounds of formula (I) or (la) or salts and solvates thereof may exist in one or more polymorphic form, which are included in the present invention.

Prodrugs of the compounds of formula (I) and (la) are included within the scope of the present invention.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I) or (la), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds defined in the first aspect which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined in the first aspect are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds of formula (I) and (la). Suitable prodrugs for compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.

The compounds of the invention have been found to exhibit antiviral activity, specifically HCV inhibitory activity, and may therefore useful in treating or preventing viral infections, such as HCV infections, or diseases associated with such infections. In vitro studies have been performed which demonstrate the usefulness of compounds described herein as antiviral agents.

The present invention provides a compound of formula (I) or (la) or a

pharmaceutically acceptable salt thereof for use in medical therapy.

The present invention provides the use of a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and/or preventing viral infections, such as HCV infections, and/or diseases associated with such infections.

The present invention provides a compound of formula (I) or (la) or a

pharmaceutically acceptable salt thereof for use in treating and/or preventing viral infections, such as HCV infections, and/or diseases associated with such infections.

The present invention provides a method for treating and/or preventing viral infections, such as HCV infections, or diseases associated with such infections which method comprises administering to a subject, for example a human, a therapeutically effective amount of a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference herein to therapy or treatment may include, but is not limited to prevention, retardation, prophylaxis, and cure of the disease. The present invention provides compounds and pharmaceutical compositions for the treatment and prevention of viral infections, such as HCV infections, as well as diseases associated with viral infections in living hosts. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection include treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

Within the context of the present invention, the terms describing the indications used herein are classified in the Merck Manual of Diagnosis and Therapy, 17^th Edition and/or the International Classification of Diseases 10 Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention.

Processes for the preparation of compounds of formula (I) form further aspects of the invention. Throughout the specification, general formulae are designated by Roman numerals (I) - (XXXVI)

Included in the current invention is a process (A) for the preparation of compounds of formula II.

(I I)

Compounds of formula (II) may be prepared by reacting compounds of formula (III) with compounds of formula (IV) where R² represents hydrogen, Ci_-6alkyl or C₃-₆cycloalkyl, according to conventional amide forming chemistry. Similarly, R² may represent a hydroxyl group, optionally protected on the hydroxyl with a suitable protecting group, for example benzyl.

(IN)

For example, the reaction may be carried out in the presence of a coupling reagent, e.g. 2-(7-azabenzotriazole-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HATU), suitably at 0 to 50^°C, e.g. room temperature. If necessary, the protecting groups present on R² , for example benzyl, may be removed via a subsequent transformation, for example exposure to hydrogen and palladium on carbon.

Compounds of formula (III) may conventionally be prepared by hydrolysis of compounds of formula (V) where R^x is Ci_-6alkyl, e.g. methyl or ethyl.

(V)

Suitable reaction conditions include treatment with alkali metal hydroxides, e.g. NaOH in a suitable solvent, e.g. THF, ethanol or mixtures thereof, at a suitable temperature, such as 0 to 100^°C, e.g. 50 to 80^°C or reflux. Compounds of formula (V) may be prepared by reacting compounds of formula (VI) with compounds of formula (VII) wherein R⁴ represents -S(0)₂R⁵ and L² represents a suitable leaving group, (such as halogen, e.g. chlorine).

by conventional alkylation or acylation conditions, for example a compound of formula (VI) may be reacted with CH₃S0₂CI, in a suitable solvent, e.g. DCM, with a suitable base, e.g. DIPEA, at a suitable temperature, such as 0 to 50^°C, e.g. 0^°C. Conventional protecting groups may be used as required for this conversion as understood by persons skilled in the art.

Compounds of formula (VI) may be prepared from compounds of formula (VIII) by conventional reduction techniques:

(VIII)

for example, by catalytic hydrogenation in the presence of a noble metal catalyst, e.g.

palladium/charcoal at atmospheric pressure, in an appropriate solvent, e.g. ethyl acetate (EtOAc), suitably at 0 to 50^°C, e.g. room temperature.

Compounds of formula (VIII) where R³ represents Ci_-6alkoxy (such as prop-2-oxy), may be prepared from compounds of formula (IX):

(IX)

by nitration with nitric acid (HN0₃) in a suitable solvent, e.g. chloroform (CHCI₃).

Compounds of formula (IX) may be prepared by reacting compounds of formula (X) with compounds of formula (X

suitably in the presence of a catalyst e.g. ZnCI₂, and in a suitable solvent, e.g. methanol (MeOH), ether, ethanol (EtOH), THF or mixtures thereof, at a suitable temperature, e.g. reflux, followed by reaction with compounds of formula (XII) where appropriate:

Y— L

(XI I )

where L³ is a leaving group such as a halogen atom, e.g. bromine, where Y represents Ci_ ₆alkyl or C₃-₆cycloalkyl and the reaction is carried out under conventional O-alkylation conditions in the presence of a suitable solvent, e.g. N-methylpyrrolidone (NMP), suitably at temperature range, such as room temperature to 100^°C, e.g. 50 to 70^°C, with a suitable base, e.g. alkali metal carbonate, e.g. Cs₂C0₃. Together, Y and the O atom to which it is attached form an R³ group selected from Ci_-6alkoxy (such as prop-2-oxy), C_3-6cycloalkoxy, C_2-6alkenyloxy or hydroxy,.

According to another process (B), compounds of formula (VIII) where R³ is C_3- ₆cycloalkyl (such as cyclopropyl), may be prepared by reaction of compounds of formula (XIII) with compounds of formula (XIV) according to conventional carbon-carbon bond cross- coupling reaction methods:

(XIII)

where L⁴ represents a suitable activating group, such as a boronic acid group, e.g. B(OH)₂, optionally in the presence of suitable cofactors, e.g. KF and NaBr, optionally in the presence of a suitable catalyst, e.g. tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), in a suitable solvent, e.g. toluene, and conducted at a suitable temperature range, such as 90 to 120^°C, e.g. reflux.

Compounds of formula (XIII) may be prepared from compounds of formula (XV):

by reaction with a triflating agent, e.g. triflic anhydride (Tf₂0) in the presence of a suitable base, e.g. Ν,Ν-diisopropylethylamine (DIPEA), a suitable nucleophilic catalyst, e.g. N- dimethylaminopyridine (DMAP), and a suitable solvent, e.g. dichloromethane (DCM), and conducted at a suitable temperature range, such as 15 to 30^°C, e.g. 0 to 10^°C.

Compounds of formula (XV) may alternatively be prepared from compounds of formula (VIII) in which R³ represents a suitable ether group by O-dealkylation. Suitable ether groups include, but are not limited to those compounds of formula (VII I) wherein R³ is C-i. ₆alkoxy (such as prop-2-oxy). Suitable conditions for the O-dealkylation process include a suitable reagent, e.g. BCI₃ in a suitable solvent, e.g. DCM, suitably at 0 to 30°C, e.g. 10 to 20°C.

According to another process (C), a compound of formula (I) or (la) may be prepared by reacting compounds of formula I I with allyllic or homoallylic leaving groups of the formula XVI or XVI I (where X = Ci_-8 alkyl) to give XVI I I or XIX. Suitable conditions for this coupling include conventional alkylation conditions wherein a base (for example potassium

carbonate), suitable solvent (for example MeCN), and temperature (for example 0-120°) are employed. Allylic halides of the type XVI and XVI I, wherein P² is a suitable alcohol protection group (for example benzyl or tert-butyl dimethyl silyl), are known in the art, or may be readily prepared by known methods for the formation of allylic leaving groups (including mesylates, halides, tosylates, etc.).

Olefins XVI I I and XIX undergo conversion to oxaboryls XX and XXI via hydroboration with a boronate of formula XXI I (where Z may represent an aryl ring to afford catechol or related molecules to afford related cyclic boronate esters) in the presence of a suitable catalyst (for example Rh(CO)(PPh₃)₂CI) and then deprotection of P² using conditions known in the art (including H₂ and Pd/C for a benzyl protecting group). When reagent XXI I includes a strongly chelating ligand (for example pinacol or catechol) it is advantageous to add a scavenger (for example polymer-supported benzene boronic acid) in the final transformation in addition to an aqueous acid (for example 6. ON HCI).

According to another process (D), a compound of formula (I) or (la) may be prepared from compounds of formula XXI I I . XXI I I may be prepared by alkylation of I I with a suitable alkylating agent, for example 2-chloroethyl phenylmethyl ether, with base, for example potassium carbonate in solvent, for example DMF followed by treatment with a suitable catalyst, for example palladium on activated carbon in the presence of a reducing agent, for example hydrogen gas.

Alkylation of XXIII using convention conditions including a suitable alkylating agent such as (XXVI or allyl-methylcarbonate), base (including, for example, triethylamine or sodium hydride), solvent (including DMF or THF), catalyst (for example palladium acetate) and temperature (from 0-120°C) affords boronic acid XXIV. Those skilled in the art will recognize that if an olefinic alkylating agent (for example allylmethylcarbonate as described above) is utilized subsequent hydroboration with a boron source (for example XXII) in the presence of a suitable catalyst (for example Rh(CO)(PPh₃)₂CI) will be necessary to afford compounds with formula XXIV. Similarly, treatment of XXIII with a suitable acylating agent (for example methanesulfonylchloride) in the presence of base (for example triethylamine) and solvent (for example dichloromethane) affords an activated mesylate which can be displaced by a suitable amine (for example methylallyl amine) which, followed by hydroboration as described above, affords compounds of structure XXV.

According to another process (E), a compound of formula I may be prepared by reacting compounds of formula XXVII, XXVIII, or XXIX (Y² = proton or methyl) with compounds of formula II under standard alkylation conditions known in the art and described above. Compounds of formula XXVII, XXVIII, and XXIX are known in the art, or may be readily prepared by known methods. Conversion of the aryl bromide functionality to the corresponding boronate can be accomplished using a suitable catalyst (for example palladium acetate), base (for example KOAc), boron source (for example bis-pinacolato diboron) and solvent (for example dioxane). Reduction of the ester functionality using a hydride source (for example DIBALH or LAH) affords compounds of formula XXX. Those skilled in the art will recognize various regioisomers of XXVII, XXVIII, and XXIX may be employed to access unique regioisomers of XXX. For alkylations involving XXIX, those skilled in the art will recognize a deprotection (for example with 6. ON HCI if P = MOM) will be substituted for the reduction step described above.

According to another process (F), a compound of formula I may be prepared by reacting compounds of formula XXXI or XXXII (where L¹ is a suitable leaving group) with compounds of formula II under standard alkylation conditions known in the art and described above. Compounds of formula XXXI and XXXII are known in the art, or may be readily prepared by known methods. Conversion of the aryl bromide functionality to the

corresponding boronate can be accomplished using a suitable catalyst (for example palladium acetate), base (for example KOAc), boron source (for example bis-pinacolato diboron) and solvent (for example dioxane). Reduction of the ester functionality using a hydride source (for example DIBALH or LAH) for XXXI or deprotection of P¹ using suitable conditions for XXXII (for example 5. ON HCI if P¹ = -MOM) affords compounds of formula XXXIII. Those skilled in the art will recognize various regioisomers of XXXI and XXXII may be employed to access unique regioisomers of XXXIII, and that by using either XXXI or XXXII one could generate XXXIII with the attachment point on the aryl or heteroaryl ring

respectively.

According to another process (G), compounds of formula XXXIV may be treated with a suitable reducing agent (for example DIBALH) in a suitable solvent (for example DCM) to afford the corresponding alcohol. Such alcohols undergo facile Mitsunobu esterification with II upon exposure to a suitable activating agent (for example DEAD) in the presence of a phosphine (for example triphenylphosphine) and solvent (for example THF) to afford XXXV. Treatment of XXXV with a suitable catalyst (for example PdCI₂(dppf)) in the presence of a base (for example potassium acetate), boron source (for example bis-pinacol-diboron), and solvent (for example dioxane) followed by exposure to strong acid (for example 6. ON HCI) affords cyclic boronates of the general type XXXVI.

The invention also extends to novel intermediates disclosed herein, used in the preparation of compounds of formula (I) and (la) or salts thereof.

Further details for the preparation of compounds of formula (I) and (la) are found in the examples section hereinafter.

Those skilled in the art will appreciate that in the preparation of compounds of formula (I) and (la) and/or salts thereof it may be necessary and/or desirable to protect one or more sensitive groups in the molecule or the appropriate intermediate to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis" by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991 ) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g.

formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g.

benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9- fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl or aralkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).

Various intermediate compounds used in the above-mentioned process, including but not limited to certain compounds of formulae (XXVI) constitute a further aspect of the present invention.

The invention also includes a pharmaceutical composition comprising a compound of formula (I) or (la) or pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable excipient. The term "excipient" refers to a compound that is useful in preparing a pharmaceutical composition, e.g. diluent, carrier.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The dosage forms and procedures may involve amporphous dispersions, molecular dispersions, hot melt extrusion, particle size reduction through micronization or wet bead milling (nanomilling), self emulsifying systems, or complexation, for example cyclodextrin.

The pharmaceutical compositions of the invention may be formulated for

administration by any route, and include those in a form adapted for oral, topical,

intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal or transmucosal administration.

For oral administration, the compounds can be formulated into any suitable dosage form, for example, tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile solutions or suspensions, syrups, elixirs and

concentrated drops.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example a hard gelatin capsule shell or a soft gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;

non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.

For injection (parenteral administration) e.g. intramuscular, intravenous,

intraperitoneal, subcutaneous, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water, saline solution, Hank's solution or Ringer's solution. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. In addition, the compounds of the invention may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.

For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories. A typical suppository formulation comprises a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional non-CFC propellant such as 1 ,1 , 1 ,2-tetrafluoroethane or 1 ,1 , 1 ,2,3,3,3-heptafluoropropane.

The topical formulations of the present invention may be presented as, for instance, ointments, creams, gels, salves or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.

Preparations may be suitably formulated to give controlled/extended release of the active compound.

The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound (IC₅o) potency, (EC₅o) efficacy, and the biological half-life (of the compound), the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.

Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of administration of the present compounds.

Preferably the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.

Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/kg, and preferably from 0.1 to 50 mg/kg, of a compound of formula (I) or (la) or a

pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of formula (I) or (la). A topical formulation contains suitably 0.01 to 5.0% of a compound of formula (I) or (la). The active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art. These sub-doses may be administered in unit dosage forms, for example, containing 0.5 - 100 mg, 5 to 1000 mg or 50 to 500 mg, or 20 to 500 mg, or 50 to 400 mg of active ingredient per unit dosage form.

It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by

conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using

conventional course of treatment determination tests.

The compounds of formula (I) or (la) or pharmaceutically acceptable salt(s) thereof may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or (la) or

pharmaceutically acceptable salt thereof together with one or more further therapeutic agent(s).

Compounds of the invention may be administered in combination with other therapeutic agents, for example immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs,

bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy.

Compounds of the invention may be administered in combination with other therapeutic anti-viral agents selected from the list: interferon, pegylated interferon, ribavirin, protease inhibitors, for example filibuvir, polymerase inhibitors, for example, boceprevir, telaprevir, or compounds disclosed in PCT/US2010/046782, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs,

immunoglobulines, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. For example, combination therapy may comprise providing a compound for formula (I) or (la) or pharmaceutically acceptable salt thereof with other anti-viral agents, such as acyclovir, famciclovir, valganciclovir and related compounds, ribavirin and related compounds, amantadine and related compounds, various interferons such as, interferon-alpha, interferon-beta, interferon-gamma and the like as well as alternative forms of interferons such as pegylated interferons.

When a compound of formula (I) or (la) or pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with at least one pharmaceutically acceptable carrier and/or excipient comprise a further aspect of the invention.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions by any convenient route.

When administration is sequential, either the HCV inhibitor or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two

compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

The following non-limiting examples illustrate the present invention. EXAMPLES

It will be appreciated by those skilled in the art that when solvents are used in reactions it is desirable to use anhydrous solvents. It is further desirable to conduct reactions under an inert atmosphere, for example under nitrogen or argon, where appropriate.

Abbreviations

DMSO Dimethylsulfoxide

HATU 0-(7-azabenzotriazol-1 -y\)-N,N,N',N -tetramethyluronium

hexafluorophosphate

ISCO Companion™ Automated flash chromatography equipment with fraction

analysis by UV absorption available from Presearch and manufactured by Teledyne Isco Inc.

THF Tetrahydrofuran Intermediate 1

Methyl 2-(4-fluorophenyl)-5-hvdroxy-1-benzofuran-3-carboxylate

Using oven dried glassware and under an atmosphere of nitrogen, anhydrous zinc chloride (25g, 183 mmol) was stirred in anhydrous methanol (60 mL) then heated to a 75 °C internal temperature. Methyl 4-fluorobenzoylacetate (39.6 g, 202 mmol) was added as a single portion followed by dropwise addition of a solution of p-benzoquinone (19.83 g, 183 mmol) in anhydrous diethyl ether (500 mL) over 4 hours. This was performed with a simultaneous distillation of ether from the reaction mixture such that the reaction volume remained approximately constant (a bath temperature of 140 °C maintained an internal temperature initially at 75°C then gradually increasing to a maximum of 1 15°C). 2.5 hours after the start of the benzoquinone addition, more methanol (20 mL) was added to facilitate stirring. After addition of benzoquinone was complete, heating of the reaction mixture at 100°C (internal) continued for 1 hour. The reaction mixture was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate (800 mL). The insoluble solids were removed from the biphasic solution by filtration and the organic layer was then separated, dried (Na₂S0₄), filtered and evaporated under vacuum. The brown residue was slurried in warm dichloromethane (-225 mL) and the mixture was left to stand in a refrigerator for 18 hours. The resulting solids were filtered from the dark brown solution, washed with a small volume of dichloromethane then dried under vacuum to give Methyl 2- (4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 285 (M-1 ). Intermediate 2

Methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxyl-1-benzofuran-3-carboxylate

A mixture of methyl 2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate

(18.86 g, 65.9 mmol), isopropyl bromide (24.74 mL, 264 mmol) and cesium carbonate (42.9 g, 132 mmol) in dry N-Methyl-2-pyrrolidone (191 mL) was stirred at 60°C under nitrogen for 20 hours. The resultant thick suspension was allowed to cool to room temperature and then 7% aqueous ammonia solution (200 mL) was added with rapid stirring. This mixture was extracted with heptane (700 mL) and then the aqueous phase was separated off. Ethyl acetate (-100 mL) was added to the organic phase and the resultant mixture was shaken and then dried over Na₂S0₄ and evaporated to give a brown oil which crystallized on standing overnight. This material was recrystallised from hot methanol and the solid was collected by filtration, washed with methanol and finally dried under vacuum to give methyl 2- (4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 329 (M+1 ). The mother liquors from the first recrystallisation were crystallized a second time to give an additional batch of Methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1 -benzofuran-3- carboxylate. Intermediate 3

Methyl 2-(4-fluorophenyl)-5-r(1 -methylethyl)oxyl-6-nitro-1-benzofuran-3-carboxylate

To a solution of methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1 -benzofuran-3- carboxylate (6.16 g, 18.76 mmol) in chloroform (22 mL) at -15 °C was added dropwise a cold solution of 70% nitric acid (1 1 mL, 172 mmol) in chloroform (22 mL). After stirring at 0°C for 1 hour, the reaction mixture was washed with water (50 mL) and the organic phase was separated by hydrophobic filter tube then evaporated under vacuum to afford a brown solid. The solid was triturated in methyl ferf-butyl ether (25 mL) and the resulting pale yellow powder was filtered off, washed with heptane and dried under vacuum to give methyl 2-(4- fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1 -benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 764 (2M+ NH₄)⁺.

Intermediate 4 Methyl 6-amino-2-(4-fluorophenyl)-5-[(1-methylethyl)oxyl-1 -benzofuran-3-carboxylate

A solution of methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-6-nitro-1 -benzofuran-3- carboxylate (391 mg, 1.047 mmol) in ethyl acetate (15 mL) was stirred with 10% palladium on carbon (1 1 1 mg, 0.105 mmol) under an atmosphere of hydrogen at 21 °C for 16 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give a brown gum. This was redissolved in a small volume of diethyl ether and re- evaporated to give the Methyl 6-amino-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1- benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 344 (M+ 1 ).

Intermediate 5

Methyl 6-[bis(methylsulfonyl)aminol-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxyl-1 -benzofuran- 3-carboxylate

To a stirred mixture of methyl 6-amino-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1- benzofuran-3-carboxylate (1 .49 g, 4.34 mmol) in dry dichloromethane (25 mL) at 0°C under nitrogen was added di-isopropylethylamine (1 .895 mL, 10.85 mmol) followed by

methanesulfonyl chloride (0.744 mL, 9.55 mmol). The reaction mixture was stirred for 1 hour and warmed to room temperature, washed with water and evaporated under vacuum to give methyl 6-[bis(methylsulfonyl)amino]-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1 -benzofuran- 3-carboxylate. LCMS {m/z, ES⁺) = 517 (M+ NH₄)⁺.

Intermediate 6

2-(4-Fluorophenyl)-5-r(1-methylethyl)oxyl-6-r(methylsulfonyl)aminol-1 -benzofuran-3- carboxylic acid

Methyl 6-[bis(methylsulfonyl)amino]-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1 - benzofuran-3-carboxylate (2.199 g, 4.40 mmol) was heated at 80°C in a mixture of methanol (20 mL), tetrahydrofuran (20.00 mL) and 2M sodium hydroxide (20 mL, 40.0 mmol) for 16 hours. The solvent was partially evaporated under vacuum and the reaction mixture was partitioned between dilute aqueous HCI and dichloromethane. The organic phase was separated by hydrophobic filter tube and evaporated to dryness to give 2-(4-Fluorophenyl)-5- [(1-methylethyl)oxy]-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxylic acid. LCMS {m/z, ES⁺) = 406 (M- H).

Intermediate 7

2- (4-Fluorophenyl)-/\/-methyl-5-r(1 -methylethyl)oxyl-6-r(methylsulfonyl)aminol-1-benzofuran-

3- carboxamide

2-(4-Fluorophenyl)-5-[(1-methylethyl)oxy]-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxylic acid (1 .738 g, 4.27 mmol) was stirred in dry N,N-dimethylformamide (20 mL) at 21 °C with di-isopropylethylamine (1.639 mL, 9.39 mmol). HATU (1.946 g, 5.12 mmol) was added and, after 10 minutes, a 2M solution of methylamine in THF (10.66 mL, 21.33 mmol) was added. The reaction mixture was stirred for 18 hours and then evaporated under vacuum. The residue was partitioned between dichloromethane and water. The organic phase was separated, passed through a hydrophobic filter tube and evaporated under vacuum. The residue was purified by ISCO Companion automated flash chromatography, eluting over silica gel with a gradient of 30-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated under vacuum to give 2-(4-Fluorophenyl)-/V-methyl- 5-[(1-methylethyl)oxy]-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide. LCMS {m/z, ES⁺) = 421 (M+ H).

Intermediate 9

Methyl 2-(4-fluorophenyl)-5-hvdroxy-6-nitro-1 -benzofuran-3-carboxylate

To a stirred solution of methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-6-nitro-1- benzofuran-3-carboxylate (5.237 g, 14.03 mmol) in dry dichloromethane (70 mL) at -15°C, under an atmosphere of nitrogen, was added a 1 M solution of boron trichloride in

dichloromethane (23.85 mL, 23.85 mmol) over 30 minutes using a syringe pump. The dark brown-red reaction mixture was poured over ice (-250 mL). The ice was allowed to melt and the mixture extracted with dichloromethane (-450 mL). The organic phase was separated by hydrophobic filter tube and evaporated under vacuum to give the methyl 2-(4-fluorophenyl)-5- hydroxy-6-nitro-1 -benzofuran-3-carboxylate. ¹H NMR (d₆-DMSO): δ 10.97 (1 H, br. s), 8.34 (1 H, s), 8.07 (2H, dd), 7.67 (1 H, s), 7.43 (2H, t), 3.86 (3H, s).

Intermediate 10

Methyl 2-(4-fluorophenyl)-6-nitro-5-{r(trifluoromethyl)sulfonylloxy}-1-benzofuran-3-carboxylate

To an ice-cooled stirred mixture of methyl 2-(4-fluorophenyl)-5-hydroxy-6-nitro-1- benzofuran-3-carboxylate (4.915 g, 14.84 mmol) and 4-(dimethylamino)pyridine (0.181 g, 1.484 mmol) in anhydrous dichloromethane (130 mL) under nitrogen, was added

triethylamine (3.10 mL, 22.26 mmol) then trifluoromethanesulfonic anhydride (3.76 mL, 22.26 mmol). After 50 minutes the reaction, still in an ice bath at 0°C, was quenched by addition of water. The reaction mixture was partitioned between dichloromethane and water and the organics were separated. The aqueous phase was extracted with more dichloromethane and the combined organics were washed with 2M HCI then water. The organics were dried by hydrophobic filter tube and evaporated to give the Methyl 2-(4-fluorophenyl)-6-nitro-5- {[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 481 (M+ NH₄)⁺.

Intermediate 1 1

Methyl 5-cvclopropyl-2-(4-fluorophenyl)-6-nitro-1 -benzofuran-3-carboxylate

Methyl 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1 -benzofuran-3- carboxylate (7.12 g, 15.37 mmol), cyclopropylboronic acid (2.19 g, 25.5 mmol), potassium fluoride (3.26 g, 56.1 mmol), sodium bromide (1.75 g, 17.01 mmol) and

tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.736 mmol) were stirred together under nitrogen in a mixture of toluene (90 mL) and water (2.25 mL) and heated at 100°C for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic phase was separated, dried by hydrophobic filter tube and evaporated under vacuum. The residue was purified by ISCO Companion automated flash chromatography, eluting over silica gel with a gradient of 0-5% ethyl acetate in cyclohexane. Product containing fractions were evaporated under vacuum to give the methyl 5-cyclopropyl-2-(4- fluorophenyl)-6-nitro-1 -benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 728 (2M+ NH₄)⁺. Intermediate 12

Meth l 6-amino-5-cvclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate

A solution of methyl 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3- carboxylate (3.175 g, 8.94 mmol) in ethyl acetate (250 mL) containing 2M HCI (17 drops) was stirred with 10% palladium on carbon (0.951 g, 0.894 mmol) under an atmosphere of hydrogen at 21 °C for 16 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give a dark green solid. This was dissolved in dichloromethane, washed with sodium bicarbonate solution, separated by hydrophobic frit, then evaporated to dryness and purified by ISCO Companion automated flash

chromatography, eluting over silica gel with a gradient of 0-30% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated under vacuum to give the methyl 6- amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 326 (M+ H).

Intermediate 13

Methyl 6-rbis(methylsulfonyl)aminol-5-cvclopropyl-2-(4-fluorophenyl)-1-benzofuran-3- rboxylate

A solution of methyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3- carboxylate (1 .96 g, 6.02 mmol) and triethylamine (2.52 mL, 18.07 mmol) in dry

dichloromethane (40 mL) was cooled (ice bath) to 0°C, then treated with methanesulphonyl chloride (1.174 mL, 15.06 mmol). The reaction was stirred at 0°C (ice bath) for 2 hours. TLC (1 :1 ethyl acetate/cyclohexane) showed no strongly KMn0₄ positive starting material remaining in the reaction mixture. Water (100 mL) was added and the organics extracted 3 times with dichloromethane, dried using an hydrophobic frit and evaporated to dryness to give the methyl 6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran- 3-carboxylate. LCMS {m/z, ES⁺) = 482 (M+ H).

Intermediate 14

5-Cvclopropyl-2-(4-fluorophenyl)-6-r(methylsulfonyl)aminol-1 -benzofuran-3-carboxylic acid

A suspension of methyl 6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)- 1-benzofuran-3-carboxylate (2.88 g, 5.98 mmol) in ethanol (50 mL) and water (25 mL) was treated with potassium hydroxide (6.71 g, 120 mmol) and heated at reflux for 1 hour (the suspension went into solution upon heating). The reaction was concentrated under vacuum, water (100 mL) was added and the solution acidified with 2M HCI (50 mL). The resulting precipitate was filtered, washed with 0.5 M HCI, then dissolved in methanol. This solution was evaporated to dryness and azeotroped twice with toluene to give 5-Cyclopropyl-2-(4- fluorophenyl)-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxylic acid. LCMS {m/z, ES⁺) = 390 (M+ H).

Intermediate 15

5-Cvclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-r(methylsulfonyl)aminol-1 -benzofuran-3- rboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1 -benzofuran- 3-carboxylic acid (2.52 g, 6.47 mmol), HATU (2.95 g, 7.77 mmol) and triethylamine (1 .984 mL, 14.24 mmol) in dry dichloromethane (100 mL) was stirred at room temperature for 1 hour, then treated with methylamine (16.18 mL, 32.4 mmol). The solution was stirred at room temperature under nitrogen for 4 hours, during which time a precipitate formed. The reaction was diluted with dichloromethane (300 mL) and sodium bicarbonate solution (200 mL) and stirred for 10 minutes. The layers were separated and the aqueous layer extracted with further dichloromethane (150 mL). The combined organics were washed with brine (200 mL), dried using an hydrophobic frit and evaporated to dryness to give an off-white solid. The crude product was slurried in dichloromethane and applied to the top of a prepacked silica gel cartridge (Biotage SNAP, 100g), then eluted using an ISCO companion automated flash chromatography apparatus, eluting with 0-100% ethyl acetate/cyclohexane. Some product eluted in the 40-60% ethyl acetate range, but a low mass was recovered from the column. The column was flushed with 10% methanol/dichloromethane, however some white solid still remained on top of the silica cartridge. The eluted product, the

methanol/dichloromethane flushed solution and the residual white solid from the top of the column were combined in a single flask and evaporated to dryness. This material was dissolved in hot methanol-chloroform (10% v/v) (there was still some insoluble solid) and loose silica gel added. The mixture was evaporated and the resulting solid dry-loaded on top of 2 x 100 g Biotage SNAP prepacked silica gel columns, without pre-equilibration of the column in the starting elution solvent, and purified using ISCO Companion automated flash chromatography, eluting with 0-10% methanol/dichloromethane. The product containing fractions were combined and evaporated to give the 5-Cyclopropyl-2-(4-fluorophenyl)-/V- methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide. LCMS {m/z, ES⁺) = 403 (M+ H). Examples

Example 1

r({2-r{2-(4-fluorophenyl)-3-r(methylamino)carbonyll-5-r(1-methylethyl)oxyl-1 -benzofuran-6- yl}(methylsulfonyl)aminolethyl}oxy)methyllboronic acid

Stage 1: 2-(4-fluorophenyl)-N-methyl-5-[(1-methylethyl)oxy]-6-((m^

[(phenylmethyl)oxy]ethyl}amino)-1-benzofuran-3-carboxamide

2-(4-fluorophenyl)-N-methyl-5-[(1 -methylethyl)oxy]-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (350 mg, 0.832 mmol,), was dissolved in acetonitrile (16 ml.) and treated with potassium carbonate (230 mg, 1 .665 mmol). Benzyl 2-bromoethylether (0.145 ml_, 0.916 mmol) was added and the mixture heated at 65 °C for 24 hours under nitrogen, following the procedure described for 2-(4-Fluorophenyl)-/V-methyl-5-[(1-methylethyl)oxy]-6- [(methylsulfonyl)(2-propen-1 -yl)amino]-1-benzofuran-3-carboxamide. The mixture was diluted with water and extracted with dichloromethane. The dichloromethane phase was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using Isco Companion automated flash chromatography, eluting over silica gel with a gradient of 10-50% ethyl acetate in hexanes. Appropriate fractions were combined and evaporated to give 2-(4-fluorophenyl)-N-methyl-5-[(1-methylethyl)oxy]-6-((methylsulfonyl){2- [(phenylmethyl)oxy]ethyl}amino)-1-benzofuran-3-carboxamide. LCMS {m/z, ES⁺) = 555 (M+ H). Stage 2: 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino

methylethyl)oxy]-1-benzofuran-3-carboxamide

A mixture of 2-(4-fluorophenyl)-N-methyl-5-[(1-methylethyl)oxy]-6-((methylsulfonyl){2- [(phenylmethyl)oxy]ethyl}amino)-1-benzofuran-3-carboxamide (340 mg, 0.613 mmol) and 100 mg of 10% Palladium on carbon (Degussa type) in methanol (5 ml.) was placed in a Buchi hydrogenator at atmospheric pressure for 2 hours. Filtered through Celite and the filtrate was evaporated under vacuum. The crude product was purified using Isco Companion automated flash chromatography, eluting over silica gel with a gradient of 50-80% ethyl acetate in hexanes. Appropriate fractions were combined and evaporated to give 2-(4- fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-5-[(1 -methylethyl)oxy]-1 - benzofuran-3-carboxamide. LCMS {m/z, ES⁺) = 465 (M+ H).

Stage 3: [({2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1-methylethyl)oxy]-1- benzofuran-6-yl}(methylsulfonyl)amino]ethyl}oxy)methyl]boronic acid

To a mixture of 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N- methyl-5-[(1 -methylethyl)oxy]-1 -benzofuran-3-carboxamide (100 mg, 0.215 mmol), and potassium carbonate (89 mg, 0.646 mmol) in dry acetonitrile (10 ml.) was added 2- (bromomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (101 mg, 0.458 mmol). The reaction was heated at 85 °C for 18 hours, diluted with dichloromethane, filtered, and concentrated. The crude product was purified using Isco Companion automated flash chromatography, eluting over silica gel with a gradient of 0-10% methanol in dichloromethane. Appropriate fractions were combined and evaporated. Further purification was accomplished by reverse phase chromatography to give [({2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1- methylethyl)oxy]-1 -benzofuran-6-yl}(methylsulfonyl)amino]ethyl}oxy)methyl]boronic acid. ¹H NMR (Methanol-d₄) δ 7.83 - 7.97 (m, 2 H), 7.50 - 7.58 (m, 1 H), 7.20 - 7.28 (m, 3 H), 4.79 (dt, J=12.1 , 6.0 Hz, 1 H), 3.82 (br. s., 2 H), 3.47 (t, J=5.6 Hz, 2 H), 3.27 (br. s., 2 H), 3.00 - 3.10 (m, 3 H), 2.93 (s, 3 H), 1.32 - 1.49 (m, 6 H), 3 exchangeable protons not seen. LCMS {m/z, ES⁺) = 523 (M- H). Example 2

5-Cvclopropyl-2-(4-fluorophenyl)-6-rr(1-hvdroxy-1 ,3-dihvdro-2, 1-benzoxaborol-6- yl)methyll(methylsulfonyl)aminol-N-methyl-1 -benzofuran-3-carboxamide

Step 1: Methyl 2-bromo-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamin

benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate.

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (52 mg, 0.130 mmol), methyl 2-bromo-4-(bromomethyl)benzoate (40 mg, 0.130 mmol, 3B Scientific Corporation) and potassium carbonate (18 mg, 0.130 mmol) in acetonitrile (8 ml.) was heated at 70 ^°C for 4 hours. The suspension was concentrated under reduced pressure, brine was added and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and purified by silica-gel chromatography (0-100 % ethyl acetate/hexanes gradient elution) to give 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1- benzoxaborol-6-yl)methyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (59 mg, 72%). ¹H NMR (CDCI₃): δ 7.81 (m, 2 H), 7.67 (m, 1 H), 7.55 (m, 1 H), 7.25-7.12 (m, 5 H), 5.80 (m, 1 H), 4.91 (m, 1 H), 4.74 (m, 1 H), 3.88 (2, 3 H), 3.02-2.94 (m, 6 H), 2.13 (m, 1 H), 1.03-0.83 (m, 3 H), 0.51 (m, 1 H); LCMS {m/z, ES⁺) = 629 (M+1 ).

Step 2: Methyl 4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-(4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yljbenzoate

A mixture of methyl 2-bromo-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-

[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate (23 mg, 0.037 mmol), (dicyclohexylphophinobiphenyl (1 mg, 3.65 μηηοΙ), and palladium acetate (0.4 mg, 1 .8 μηηοΙ), were dissolved in dioxane (3 ml_), pinacolborane (1 ml.) and triethylamine (0.02 ml_, 0.1 10 mmol) were added and the mixture was immersed in a 100 ^°C oil bath. The reaction was heated two hours, concentrated under reduced pressure and purified by reverse-phase hplc to give Methyl 4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate as a white solid (1 1 mg, 45%). ¹H NMR (CDCIs): δ 7.83 (m, 3 H), 7.32-7.13 (m, 6 H), 5,73 (m, 1 H), 5.02 (m, 1 H), 4.73 (m, 1 H), 3.87 (m, 3 H), 3.03-2.96 9 (m, 6 H), 2.19 (m, 1 H), 1 .34 (s, 12 H), 1.03-0.83 (m, 3 H), 0.53 (m, 1 H); LCMS {m/z, ES⁺) = 677 (M+1 ). Step 3: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[( 1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-6- yl)methyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide.

Methyl 4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]methyl}-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (1 1 mg, 0.016 mmol) was dissolved in THF (2 mL) and cooled to 0 ^°C. A solution of lithium aluminium hydride (0.03 mL, 1 M in THF) was added and the mixture was stirred 30 minutes, then poured over ice water and diluted with ethyl acetate and Rochelle's salt and stirred 30 minutes. The aqueous layer was extracted with ethyl acetate, the combined organics were washed with brine and dried over sodium sulphate. Purification by reverse -phase hplc gave 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-6- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide as a white solid (5 mg, 57%). ¹ H NMR (CDCI₃): δ 7.81 (m, 2 H), 7.56 (s, 1 H), 7.38 (m, 1 H), 7.25-7.13 (m, 5 H). 5.75 (m, 1 H), 5.03 (m 3 H), 4.79 (m, 3 H), 3.01 (s, 1 H), 2.96 (m, 3 H), 2.19 (m, 1 H), 1.02 (m, 1 H), 0.87 (m, 1 H), 0.49 (m, 1 H); LCMS {m/z, ES⁺) = 549 (M+1 ). Exchangeable Protons not observed.

Example 3

5-Cvclopropyl-2-(4-fluorophenyl)-6-[[(1-hvdroxy-1 ,3-dihydro-2, 1-benzoxaborol-4- l)methyll(methylsulfonyl)aminol-N-methyl-1 -benzofuran-3-carboxamide

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide was prepared in a manner similar to that described for 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3- dihydro-2, 1-benzoxaborol-6-yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3- carboxamide from 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (18 mg, 0.045 mmol) and methyl 3-(bromomethyl)-2- iodobenzoate (17 mg, 0.048 mmol; Eur. JMC. 2005, 40(7), 615) in 3 steps as a white solid after purification by reverse-phase hplc.¹H NMR (CDCI₃): δ 7.80 (m, 2 H), 7.61 (m, 1 H), 7.23-7.12 (m, 6 H), 5.78 (m, 1 H), 4.96-4.77 (m, 4 H), 3.01 (s, 3 H), 2.94 (m, 3 H), 2.04 (m, 1 H), 0.92 (m, 1 H), 0.82 (m, 1 H), 0.63 (m, 1 H), 0.22 (m, 1 H); LCMS {m/z, ES⁺) = 549 (M+1 ). Exchangeable Protons not observed. Example 4

5-Cvclopropyl-2-(4-fluorophenyl)-6-[[(1-hvdroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- l)methyll(methylsulfonyl)aminol-N-methyl-1 -benzofuran-3-carboxamid

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide was prepared in a manner similar to that described for 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3- dihydro-2, 1-benzoxaborol-6-yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3- carboxamide from 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (124 mg, 0.308 mmol) and methyl 5-(bromomethyl)-2- iodobenzoate (109 mg, 0.308 mmol, JOC, 1990, 55(7), p. 2064) in 3 steps as a white solid after purification by reverse-phase hplc. ¹ H NMR (CDCI₃): δ 7.79 (m, 2 H), 7.61 (m, 1 H), 7.23-7.1 1 (m, 6 H), 5.73 (m, 1 H), 5.05-4.94 (m, 4 H), 4.74 (m, 1 H), 2.99 (s,3 H), 2.95 (m, 3 H), 2.16 (m, 1 H), 0.99 (m, 1 H), 0.86 (m, 2 H), 0.49 (m, 1 H); LCMS {m/z, ES⁺) = 549 (M+1 ). Exchangeable Protons not observed.

Example 5

2-(4-Fluorophenyl)-6-rr(1-hvdroxy-1 ,3-dihvdro-2, 1-benzoxaborol-4- yl)methyll(methylsulfonyl)aminol-N-methyl-5-r(1-methylethyl)oxyl-1-benzofuran-3- carboxamide

2-(4-Fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-4- yl)methyl](methylsulfonyl)amino]-N-methyl-5-[(1-methylethyl)oxy]-1-benzofuran-3- carboxamide was prepared in a manner similar to that described for 5-Cyclopropyl-2-(4- fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1 -benzoxaborol-6- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide from 2-(4- fluorophenyl)-N-methyl-5-[(1 -methylethyl)oxy]-6-[(methylsulfonyl)amino]-1-b^ carboxamide (148 mg, 0.352 mmol) and methyl 2-(bromomethyl)-6-iodobenzoate (125 mg, 0.352 mmol, Eur. J. Med. Chem., 2005, 40(7), p. 615) in 3 steps as a white solid after purification by reverse-phase hplc. ¹H NMR d₆-DMSO: δ 9.16 (s, 1 H), 8.41 (m, 1 H), 7.87 (m, 2 H), 7.56 (m, 1 H), 7.41 (s, 1 H), 7.34 (m, 2 H), 7.22 (m, 2 H), 7.06 (s, 1 H), 5.09-4.74 (m, 4 H), 3.13 (s, 3 H), 2.79 (m, 3 H), 1.34 (br s, 6 H); LCMS {m/z, ES⁺) = 567 (M+1 ).

Exchangeable Protons not observed.

Example 6

2-(4-Fluorophenyl)-6-rr(1-hvdroxy-1 ,3-dihvdro-2, 1-benzoxaborol-5- yl)methyll(methylsulfonyl)aminol-N-methyl-5-r(1-methylethyl)oxyl-1-benzofuran-3- carboxamide

2-(4-Fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-N-methyl-5-[(1-methylethyl)oxy]-1-benzofuran-3- carboxamide was prepared in a manner similar to that for 5-Cyclopropyl-2-(4-fluorophenyl)-6- [[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-6-yl)methyl](methylsulfonyl)amino]-N-methyl-1- benzofuran-3-carboxamide from 2-(4-fluorophenyl)-N-methyl-5-[(1-methylethyl)oxy]-6- [(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (961 mg, 2.29 mmol) and methyl 5- (bromomethyl)-2-iodobenzoate (1.10 g, 3.09 mmol) in 3 steps as a white solid after purification by reverse-phase hplc. ¹H NMR (CDCI₃): δ 7.70 (m, 2 H), 7.57 (m, 2 H), 7.37 (s, 1 H), 7.27-7.1 1 (m, 5 H), 5.69 (m, 1 H), 5.09-4.50 (m, 5 H), 3.02 (s, 3 H), 2.91 (m, 3 H), 1.45 (m, 6 H); LCMS {m/z, ES⁺) = 567 (M+1 ). Example 7

5-Cvclopropyl-2-(4-fluorophenyl)-6-rr(2-hvdroxy-1 ,2-oxaborolan-4- yl)methyll(methylsulfonyl)aminol-N-methyl-1 -benzofuran-3-carboxamide

Step 1 : 3-chloro-2-(chloromethyl)prop-1 -ene

A solution of thionyl chloride (290 g, 1 19 mmol) in DCM (200 mL) was added dropwise into a mixture of 2-methylenepropane-1 ,3-diol (88 g, 1 mol), dry pyridine (150 mL), and dry DCM (100 mL). The reaction mixture was heated to reflux with stirring for 3 hours and then allowed to stand overnight. The mixture was cooled to room temperature and poured into ice. The solution was neutralized with solid sodium bicarbonate and then extracted with diethyl ether(3 <0.6 L) followed by washing the ether extracts with dilute sulfuric acid. The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue which was fractionated to give 3-chloro-2- (chloromethyl)prop-l -ene (40.1 g, 32%) as a colorless oil.

Step 2: ((2-(chloromethyl)allyloxy)methyl)benzene

To an over-dried flask was added DME (240 mL), sodium hydride (4.12 g, 120 mmol), and then benzyl alcohol (12.4 mL, 120 mmol) was added dropwise. After the addition was complete the mixture was heated to reflux for 1 hour. The mixture was cooled to 0 °C in an ice-water bath and 3-chloro-2-(chloromethyl)prop-1-ene (12.7 mL, 120 mmol) was added in one portion. The mixture was heated to reflux for 19 hours, cooled to room temperature, and poured into saturated sodium hydrogen carbonate solution (250 mL). The aqueous layer was extracted with diethyl ether (4x200 mL). The combined organic layers were dried with anhydrous sodium sulphate, filtered, and concentrated in vacuo to give a residue which was fractionated to give ((2-(chloromethyl)allyloxy)methyl)benzene (10.7 g, 45.5%) as a colorless oil. LCMS (m/z, ES⁺) = 219 (M+1 ) Step 3: ({[2-(bromomethyl)-2-propen-1-yl]oxy}methyl)benzene

To an over-dried flask were added (2-chloromethylallyloxymethyl)benzene (8.70 g, 44.4 mmol), Aliquat 336 (1 mL, 2.22 mmol), dry THF (22.6 mL) and anhydrous LiBr (7.72 g, 88.78 mmol). The reaction mixture was stirred in a 60 °C oil bath for 2 hours and then cooled to ambient temperature. The mixture was filtered using Florisil and washed with diethyl ether. The volatiles were removed in vacuo to afford ({[2-(bromomethyl)-2-propen-1- yl]oxy}methyl)benzene (6.53 g, 60%) as a colorless oil. LC-MS (m/z, ES⁺) = 223 (M+1 ) Step 4: 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)(2- {[(phenylmethyl)oxy]methyl}-2-propen-1-yl)amino]-5,6-dihydro-1-benzo

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]- 1-benzofuran-3-carboxamide (1.400 g, 3.48 mmol), ({[2-(bromomethyl)-2-propen-1- yl]oxy}methyl)benzene (1 .258 g, 5.22 mmol), and potassium carbonate (1.442 g, 10.44 mmol) in acetonitrile (50 ml.) was maintained with stirring at 80°C for 3 hours. The mixture was concentrated under reduced pressure and diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)- N-methyl-6-[(methylsulfonyl)(2-{[(phenylmethyl)oxy]methyl}-2-propen-1-yl)amino]-1 - benzofuran-3-carboxamide (1.70 g, 3.02 mmol, 87 % yield) as a white foam. LCMS {m/z, ES⁺) = 563 (M+1 ). Step 5: 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-( (methylsulfonyl){3-[(phenylmethyl)oxy]- 2-[(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)methyl]propyl}amino)-5, 6-dihydro- 1- benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)(2- {[(phenylmethyl)oxy]methyl}-2-propen-1-yl)amino]-1-benzofuran-3-carboxamide (1 .58 g, 2.81 mmol) and Rh(CO)CI(PPh₃)₂ (0.194 g, 0.281 mmol) in tetrahydrofuran (30 ml.) was treated with HBPIN (2.426 ml_, 16.85 mmol) and maintained with stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (0-40% EtOAc/Hex) to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- ((methylsulfonyl){3-[(phenylmethyl)oxy]-2-[(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl]propyl}amino)-1-benzofuran-3-carboxamide (1.63 g, 2.360 mmol, 84 % yield) as a white foam. LCMS {m/z, ES⁺) = 691 (M+1 ).

Step 6: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy- 1, 2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-((methylsulfonyl){3-

[(phenylmethyl)oxy]-2-[(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl]propyl}amino)-1- benzofuran-3-carboxamide (1.25 g, 1 .810 mmol) and 10% Pd/C (Degussa Type, 750 mg,) in tetrahydrofuran (50 ml.) was maintained under 50 psi H₂ gas for 16 hours with rapid stirring. The mixture was purged with nitrogen, filtered through celite, and the celite washed with additional THF and methylene chloride. The filtrates were concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran and treated with 5. ON HCI (aq) (2.53 ml_, 12.67 mmol) and polymer supported-benzene boronic acid (2.6 mmol/g) (3.48 g, 9.05 mmol). The suspension was stirred for 2 hours, filtered, and concentrated under reduced pressure to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide (973 mg, 1 .945 mmol, quant, yield) as a white foam. ¹H NMR (CDCI₃): 7.83 (m, 2 H), 7.44 (m, 1 H), 7.26- 7.14 (m, 3 H), 5.71 (m, 1 H),4.30-4.06 (m, 2 H), 3.90-3.62 (m, 3 H), 2.96 (m, 3 H), 2.58-2.27 (m, 2 H), 1.23 (m, 2 H), 1 .15-1.06 (m, 3 H), 0.95-0.67 (m, 3 H); LCMS {m/z, ES⁺) = 501 (M+1 ). One exchangeable proton not observed.

Example 8 & 9

(+) and (-)-5-Cvclopropyl-2-(4-fluorophenyl)-6-rr(2-hvdroxy-1 ,2-oxaborolan-4- yl)methyll(methylsulfonyl)aminol-N-methyl-1 -benzofuran-3-carboxamide

(±)-5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide

was resolved into individual enantiomers via dissolution in 1 :1 chloroform:methanol and separated using supercritical fluid chromatography (25% MeOH/C0₂, 140 bar, 10 mL/min, ChiralPak IC 10 x 250 mm, 254 nM) affording 241 mg and 298 mg of early and later eluting enantiomers respectively. Early Eluting Enantiomer: ¹H NMR (CHLOROFORM-d) δ: 7.78 - 7.95 (m, 2H), 7.47 (d, J = 7.6 Hz, 1 H), 7.29 (d, J = 2.1 Hz, 1 H), 7.20 (m, 2H), 5.75 (br. s., 1 H), 4.32 (br. s., 1 H), 4.05 - 4.21 (m, 1 H), 3.54 - 4.00 (m, 3H), 2.91 - 3.14 (m, 6H), 2.17 -

2.68 (m, 2H), 1 .03 - 1.25 (m, 3H), 0.66 - 1 .02 (m, 3H). LCMS {m/z, ES⁺) = 501 (M+1 ). Later Eluting Enantiomer: ¹H NMR (CHLOROFORM-d) d: 7.78 - 7.95 (m, 2H), 7.47 (d, J = 7.6 Hz, 1 H), 7.29 (d, J = 2.1 Hz, 1 H), 7.13 - 7.24 (m, 2H), 5.76 (d, J = 3.7 Hz, 1 H), 4.36 (br. s., 1 H), 4.04 - 4.22 (m, 1 H), 3.56 - 4.01 (m, 3H), 2.87 - 3.13 (m, 6H), 2.21 - 2.66 (m, 2H), 1.05 - 1.25 (m, 3H), 0.63 - 1 .05 (m, 3H). LCMS {m/z, ES⁺) = 501 (M+1 ).

Example 10

[({3-[{5-cvclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolpropyl}oxy)methyllboronic acid

Step 1 : 5-cyclopropyl-2- ( 4-fluorophenyl) -N-me thyl-6-( ( me thylsulfonyl) {3- [(phenylmethyl)oxy]propyl}amino)-1-benzofuran-3-carboxamide

Potassium carbonate (0.209g, 1.5 mmol) and benzyl 3-bromopropyl ether (0.198 ml_, 1.1 mmol) were added to a suspension of 5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6- [(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (201 mg, 0.5 mmol) in acetonitrile (5.5 ml. total volume). The mixture was heated at reflux for 2.5 h. The mixture was diluted with water (5 ml.) and extracted three times with dichloromethane (30 ml. total). The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by column chromatography to obtain 5-cyclopropyl-2-(4-fluorophenyl)-/V- methyl-6-((methylsulfonyl){3-[(phenylmethyl)oxy]propyl}amino)-1-benzofuran-3-carboxamide (334 mg, quant, yield), as a colorless oil. LCMS {m/z, ES⁺) = 551 (M+1 ).

Step 2: 5-cyclopropyl-2-(4-fluorophenyl)-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-/\/- methyl-1 -benzofuran-3-carboxamide

10% palladium on carbon (0.12g) was added to a mixture of 5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-6-((methylsulfonyl){3-[(phenylmethyl)oxy]propyl}amino)-1-benzofuran- 3-carboxamide (270 mg, 0.49 mmol) in ethyl acetate (24.4 ml_). The mixture was shaken under 0.4 MPa of hydrogen gas on a Parr Shaker for 25 hours. The mixture was filtered through celite which was rinsed with ethyl acetate and methanol. The filtrate was

concentrated under reduced pressure and the crude product was purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-[(3- hydroxypropyl)(methylsulfonyl)amino]-/\/-methyl-1-benzofuran-3-carboxamide as a thick oil. The oil was dissolved in ethyl acetate and triturated via addition of petroleum ether to afford a white solid (125 mg, 55% Yield). LCMS {m/z, ES⁺) = 461 (M+1 ).

Step 3: [({3-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]propyl}oxy)methyl]boronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(3- hydroxypropyl)(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (100 mg, 0.217 mmol), 2-(bromomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (120 mg, 0.543 mmol, CombiBlocks), and potassium carbonate (90 mg, 0.651 mmol) in acetonitrile (5 mL) was maintained at 80 °C for 6 hours. The mixture was cooled, diluted with dichloromethane, and filtered through celite. The filtrates were concentrated under reduced pressure, purified by column chromatography, and further purified by reverse phase hplc to afford [({3-[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]propyl}oxy)methyl]boronic acid (38 mg, 0.073 mmol, 33.8 % yield) as a white foam. ¹H NMR (CHLOROFORM-d) δ: 7.79 - 7.95 (m, 2H), 7.51 (s, 1 H), 7.31 (s, 1 H), 7.1 1 - 7.25 (m, 2H), 5.68 - 5.89 (m, 1 H), 5.00 (br. s., 1 H), 3.71 - 3.97 (m, 2H), 3.42 - 3.62 (m, 2H), 3.21 (s, 2H), 3.02 (s, 3H), 3.00 (d, J = 5.1 Hz, 3H), 2.21 - 2.40 (m, 1 H), 1 .73 - 1.90 (m, 2H), 1 .64 (br. s., 1 H), 1 .03 - 1 .16 (m, 2H), 0.88 - 1 .01 (m, 1 H), 0.72 (dd, 1 H). LCMS {m/z, ES⁺) = 519 (M+1 ).

Example 1 1

r3-({2-r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolethyl}oxy)propyllboronic acid

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsulfonyl)[2-(2-propen-1- yloxy)ethyl]amino}-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2- hydroxyethyl)(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (228 mg, 0.51 1 mmol, PCT Int. Appl. 2004, WO 2004041201 ), BINAP (63.6 mg, 0.102 mmol), Pd₂(dba)₃ (46.8 mg, 0.051 mmol), and allyl methyl carbonate (0.087 mL, 0.766 mmol) in tetrahydrofuran (5 mL) was maintained at room temperature for 16 hours. The mixture was mixed with celite, quenched with methanol, concentrated under reduced pressure, and purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsulfonyl)[2-(2- propen-1-yloxy)ethyl]amino}-1 -benzofuran-3-carboxamide (168 mg, 0.345 mmol, 67.6 % yield) as a white foam. Step 2: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfo^

tetramethyl-1 ,3, 2-dioxaborolan-2-yl)propyl]oxy}ethyl)amino]- 1-benzofuran-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsulfonyl)[2-(2- propen-1-yloxy)ethyl]amino}-1 -benzofuran-3-carboxamide (127 mg, 0.261 mmol) and Rh(CO)CI(PPh₃)₂ (18.01 mg, 0.026 mmol) in tetrahydrofuran (8 ml.) was treated dropwise with HBPIN (0.783 ml_, 0.783 mmol) and maintained with stirring for 6 hours. The mixture was concentrated onto celite and purified by column chromatography to afford 5-cyclopropyl- 2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)(2-{[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)propyl]oxy}ethyl)amino]-1 -benzofuran-3-carboxamide (142 mg, 0.162 mmol, 62.0 % yield) contaminated with 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsulfonyl)[2- (propyloxy)ethyl]amino}-1-benzofuran-3-carboxamide (roughly 2:1 ).

Step 3: [3-({2-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]ethyl}oxy)propyl]boronic acid

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)(2-{[3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)propyl]oxy}ethyl)amino]-1-benzofuran-3- carboxamide (140 mg, 0.137 mmol), polymer-supported benzeneboronic acid (1050 mg, 2.73 mmol), and 1 .0N HCI (aq) (2.73 ml_, 2.73 mmol) in tetrahydrofuran (15 mL) was maintained with stirring for 16 hours. The mixture was filtered through celite, concentrated under reduced pressure, and purified by column chromagraphy (MeOH required for product to elute) to afford [3-({2-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 - benzofuran-6-yl}(methylsulfonyl)amino]ethyl}oxy)propyl]boronic acid (22 mg, 0.041 mmol, 30% yield) as a white foam. ¹H NMR (CHLOROFORM-d) δ: 7.82 - 7.97 (m, 2H), 7.51 (s, 1 H), 7.32 (s, 1 H), 7.13 - 7.24 (m, 1 H), 5.70 - 5.87 (m, 1 H), 3.99 - 4.21 (m, 1 H), 3.75 - 3.89 (m, 1 H), 3.41 - 3.65 (m, 5H), 3.1 1 (s, 3H), 3.00 (d, J = 4.9 Hz, 3H), 2.23 - 2.42 (m, 1 H), 1.63 - 1.80 (m, 2H), 1 .19 - 1 .34 (m, 1 H), 1.03 - 1 .16 (m, 2H), 0.64 - 0.99 (m, 3H), (2 exchangeable protons not evident). LCMS {m/z, ES⁺) = 533 (M+1 ).

Example 12

r({2-r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolethyl}oxy)methyllboronic acid

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2- hydroxyethyl)(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (150 mg, 0.336 mmol) and 2-(bromomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (186 mg, 0.840 mmol) in potassium carbonate (139 mg, 1 .008 mmol) in acetonitrile (5 mL) was maintained at reflux for 24 hours. The mixture was cooled, diluted with dichloromethane, filtered through celite, and concentrated under reduced pressure. The residue was purified by reverse phase hplc to afford [({2-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]ethyl}oxy)methyl]boronic acid (65 mg, 0.129 mmol, 38.4 % yield) as a white foam. ¹H NMR (CHLOROFORM-d) δ: 7.78 - 7.95 (m, 2H), 7.60 (s, 1 H), 7.34 (s, 1 H), 7.1 1 - 7.24 (m, 2H), 5.79 (br. s., 1 H), 3.07 - 3.79 (m, 6H), 2.92 - 3.05 (m, 6H), 2.20 - 2.39 (m, 1 H), 1 .02 - 1 .18 (m, 2H), 0.87 - 1 .00 (m, 1 H), 0.60 - 0.84 (m, 1 H) (2 exchangeable proton not evident). LCMS {m/z, ES⁺) = 505 (M+1 ).

Example 13

{3-r{2-r{2-(4-fluorophenyl)-3-r(methylamino)carbonyll-5-r(1-methylethyl)oxyl-1 -benzofuran-6- l}(methylsulfonyl)aminolethyl}(methyl)aminolpropyl}boronic acid

Step 1: 2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[( 1-methylethyl)oxy]-1- benzofuran-6-yl}(methylsulfonyl)amino]ethyl methanesulfonate

A solution of 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-5- [(1-methylethyl)oxy]-1 -benzofuran-3-carboxamide (312 mg, 0.672 mmol) and DIPEA (0.352 mL, 2.015 mmol) in Dichloromethane (DCM) (10 mL) at 0°C was treated with MsCI (0.092 mL, 1 .175 mmol) and maintained with stirring at 0°C for 2 hours. The solution was poured into saturated sodium bicarbonate and the organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1- methylethyl)oxy]-1 -benzofuran-6-yl}(methylsulfonyl)amino]ethyl methanesulfonate (294 mg, 0.542 mmol, 81 % yield) as a white foam. LCMS {m/z, ES⁺) = 543 (M+1 ). Step 2: 2-(4-fluorophenyl)-N-methyl-5-[(1-methylethyl)oxy]-6-[{2-^

yl)amino]ethyl}(methylsulfonyl)amino]-1-benzofuran-3-carboxamide

A suspension of 2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 - methylethyl)oxy]-1 -benzofuran-6-yl}(methylsulfonyl)amino]ethyl methanesulfonate (284 mg, 0.523 mmol), potassium carbonate (217 mg, 1 .570 mmol), and methyl allyl amine (1.003 mL, 10.47 mmol) in N,N-dimethylformamide (5 mL) was maintained with stirring at 80 °C in a sealed pressure flask for 48 hours (with additional methyl allyl amine (1.003 mL, 10.47 mmol) added at 24 hours). The solution was cooled, poured into ethyl acetate, and washed successively with 5% LiCI (aq) and saturated sodium chloride (aq). The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 2-(4-fluorophenyl)-N-methyl-5-[(1-methylethyl)oxy]-6-[{2- [methyl(2-propen-1-yl)amino]ethyl}(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (132 mg, 0.255 mmol, 49 % yield) as a white foam. LCMS {m/z, ES⁺) = 518 (M+1 ). Step 3: {3-[{2-[{2-(4-fluorophenyl)-3-[(methylamino)carbony^

benzofuran-6-yl}(methylsulfonyl)amino]ethyl}(methyl)amino]propyl}boronic acid

A solution of 2-(4-fluorophenyl)-N-methyl-5-[(1-methylethyl)oxy]-6-[{2-[methyl(2- propen-1-yl)amino]ethyl}(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (1 10 mg, 0.213 mmol) and Rh(CO)CI(PPh3)2 (7.33 mg, 10.63 mol) in tetrahydrofuran (5 mL) was treated with 1 M HBPIN solution in THF (0.638 mL, 0.638 mmol) and maintained with stirring at room temperature for 15 hours. The mixture was concentrated under reduced pressure and purified by reverse phase hplc to afford a mixture of boronic acid contaminated with the pinacol boronate. The residue was dissolved in THF (5 mL) and 5. ON HCI (aq) (1 mL) was added. Polymer-supported benzene boronic acid (3.9 mmol/g, 400 mg) was added and the suspension was maintained with rapid stirring for 24 hours. The mixture was filtered through celite, the solids washed with acetonitrile/water, and the filtrates concentrated under reduced pressure and purified again by reverse phase hplc to afford {3-[{2-[{2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-5-[(1-methylethyl)oxy]-1-benzofuran-6- yl}(methylsulfonyl)amino]ethyl}(methyl)amino]propyl}boronic acid (6 mg, 10.65 mol, 5% yield) as a white foam. ¹H NMR (METHANOL-d₄) δ: 7.82 - 7.96 (m, 2H), 7.62 (s, 1 H), 7.1 1 - 7.34 (m, 3H), 4.13 (br. s., 1 H), 3.80 (br. s., 1 H), 3.05 (s, 3H), 2.98 (br. s., 2H), 2.94 (s, 3H), 2.78 (br. s., 3H), 2.60 (br. s., 4H), 1.55 - 1 .69 (m, 2H), 1.45 (d, 6H), 0.74 (m, 2H). LCMS {m/z, ES⁺) = 564 (M+1 ). Example 14

5-ethyl-2-(4-fluorophenyl)-6-[[(2-hvdroxy-1 ,2-oxaborolan-4-yl)methyll(methylsulfonyl)aminol- A/-methyl-1-benzofuran-3-carboxamide

Step 1 : 5-ethyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl) (2- {[(phenylmethyl)oxy]methyl}-2^ropen-1-yl)amino]-1-benzofuran-3-carboxamide

Potassium carbonate (642 mg, 4.65 mmol) and ({[2-(bromomethyl)-2-propen-1- yl]oxy}methyl)benzene (825 mg, 3.44 mmol) were added to a suspension of 5-ethyl-2-(4- fluorophenyl)-/V-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (600 mg, 1.54 mmol, PCT Int. Appl. 2004, WO 2004041201 ) in acetonitrile (7.5 mL). The mixture was maintained at reflux overnight, cooled, diluted with water, and extracted with

dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, concentrated, and the residue purified by column chromatography to obtain 5-ethyl-2-(4- fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]-/\/-methyl-1- benzofuran-3-carboxamide (180 mg, 21 % Yield) as a white solid. LCMS {m/z, ES⁺) = 551 (M+1 ). Step 2: 5-ethyl-2-(4-fluorophenyl)^-methyl-6-((methylsulfonyl){3-[(phen

[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]propyl}amino)-1-benzofuran-3- carboxamide

A mixture of 5-ethyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-/V-methyl-1 -benzofuran-3-carboxamide (330 mg),

[lr(COD)CI)]₂ (40 mg), and DPPE (47 mg) were suspended in THF (18 mL). The mixture was cooled to 0°C under nitrogen and HBPIN (767mg) was added. The mixture was stirred at room temperature for 48 hours. The solution was filtered through celite and the filtrate was diluted with ethyl acetate and water and stirred for 5 minutes. The organic layers were washed with brine and dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by prep-hplc to afford 5-ethyl-2-(4-fluorophenyl)-/V-methyl-6- ((methylsulfonyl){3-[(phenylmethyl)oxy]-2-[(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl]propyl}amino)-1-benzofuran-3-carboxamide (220 mg, 54% yield). LCMS {m/z, ES⁺) = 679 (M+1 ). Step 3: 5-ethyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

A solution of 5-ethyl-2-(4-fluorophenyl)-/V-methyl-6-((methylsulfonyl){3- [(phenylmethyl)oxy]-2-[(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl]propyl}amino)-1- benzofuran-3-carboxamide (220 mg, 0.32 mmol) in ethyl acetate was stirred with Pd/C (140 mg) under 0.4MPa hydrogen for 48 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give a white solid which was purified by prep-hplc to afford 5-ethyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4- yl)methyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide (60 mg, 38% Yield). ¹H NMR (300 MHz, MeOD) δ: 7.96(m, 2H), 7.72 (m, 2H), 7.27 (m, 2H), 3.71 (m, 4H),2.98 (m, 3H),2.94 (m, 5H), 2.05(m, 1 H), 1 .34(m, 3H),0.98(m, 2H). LCMS {m/z, ES⁺) = 489 (M+1 ). Two exchangeable protons not evident. Example 15

2-(4-fluorophenyl)-6-rr(2-hvdroxy-1 ,2-oxaborolan-4-yl)methyll(methylsulfonyl)aminol-/\/- methyl-5-(1 -methylethyl)-1 -benzofuran-3-carboxamide

Step 1: ethyl 2-(4-fluorophenyl)-5-(1 -methylethenyl)-6-nitro-1 -benzofuran-3-carboxylate

A solution of ethyl 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1 - benzofuran-3-carboxylate (2.27g, 4.77 mmol), KF (0.910 g, 24 mmol), NaBr (0.488 g, 9.54 mmol), 1 -propenyl boronic acid (0.613 g, 7.1 mmol), and Pd(PPh₃)₄ (274 mg, 0.24 mmol) were dissolved in toluene and water (24 ml_). The flask was purged with nitrogen and refluxed under nitrogen for 25 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by trituration with diethyl ether to give ethyl 2-(4-fluorophenyl)-5-(1-methylethenyl)-6-nitro-1 -benzofuran-3- carboxylate (1 .5g, 85% Yield) as a yellow solid. LCMS {m/z, ES⁺) = 370 (M+1 ).

Step 2: ethyl 6-amino-2-(4-fluorophenyl)-5-(1-methylethyl)-1-benzofuran-3-carboxylate

A solution of ethyl 2-(4-fluorophenyl)-5-(1-methylethenyl)-6-nitro-1 -benzofuran-3- carboxylate (1 .5g) in ethyl acetate was stirred with Pd/C (0.75 g) under an atmosphere of hydrogen gas at room temperature for 12 hours. The mixture was filtered through celite and the filtrates were evaporated under reduced pressure. The resulting solids were washed with diethyl ether to afford ethyl 6-amino-2-(4-fluorophenyl)-5-(1 -methylethyl)-1 -benzofuran-3- carboxylate (1 .1 g, 79% Yield) as a pale yellow solid. LCMS {m/z, ES⁺) = 342 (M+1 ). Step 3: 2-(4-fluorophenyl)-5-(1-methylethyl)-6-[(methylsulfonyl)amino]-1-ben

carboxylic acid

Methanesulfonyl chloride (0.6 ml_, 1 1 .3 mmol) was added to a chilled solution (0°C ice/water bath) of ethyl 6-amino-2-(4-fluorophenyl)-5-(1-methylethyl)-1-benzofuran-3- carboxylate (1 .1 g, 3.22 mmol) in dichloromethane. The mixture was treated with DIPEA (1 .3 ml_, 8.1 mmol) and maintained with stirring upon warming to room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, and evaporated to give a yellow solid. The solids were dissolved in ethanal and potassium hydroxide (4.56 g, 80 mmol) and water were added. The mixturewasmaintained at reflux for 0.5 hours and then concentrated under reduced pressure. The remaining solids are dissolved in water and the solutionwasacidified with 1 N HCI until a precipitate forms. The solids are collected via vacuum filtration to afford 2-(4-fluorophenyl)-5-(1-methylethyl)-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxylic acid as a white solid (1 .25 g, 80% Yield.) LCMS {m/z, ES⁺) = 392 (M+1 ).

Step 4: 2-(4-fluorophenyl)-N-methyl-5-(1-methylethyl)-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide

A solution of 2-(4-fluorophenyl)-5-(1-methylethyl)-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxylic acid (1 .25 g, 3.2 mmol) in DMF was treated with triethylamine (0.98 ml_), HATU (1.46 g), and methylamine (0.8 ml. of a 2N solution) and the solution was stirred under nitrogen for 15 hours. The mixture was concentrated under reduced pressure and the resulting oil was dissolved in dichloromethane and 2.0M HCI (aq). The organic layer was separated, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by trituration with diethyl ether to give 2-(4-fluorophenyl)-/V-methyl-5-(1 -methylethyl)- 6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (0.98g, 76% Yield) as a yellow solid. LCMS {m/z, ES⁺) = 405 (M+1 ).

Step 5: 2-(4-fluorophenyl)^-methyl-5-(1-methylethyl)-6-[(methylsu

{[(phenylmethyl)oxy]methyl}-2-propen-1-yl)amino]-1-benzofuran-3-carboxamide

Potassium carbonate (516 mg, 3.74 mmol) and ({[2-(bromomethyl)-2-propen-1 - yl]oxy}methyl)benzene (663 mg, 2.76 mmol) were added to a suspension of 2-(4- fluorophenyl)-/V-methyl-5-(1-methylethyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3- carboxamide (500 mg, 1 .24 mmol) in acetonitrile (6 ml_). The mixture was maintained with stirring at reflux overnight, cooled, diluted with water, and extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 2-(4-fluorophenyl)- A/-methyl-5-(1 -methylethyl)-6-[(methylsulfonyl)(2-{[(phenylmethyl)oxy]methyl}-2-propen-1- yl)amino]-1 -benzofuran-3-carboxamide as a white solid (620 mg, 89% Yield). LCMS {m/z, ES⁺) = 565 (M+1 ).

Step 6: 2-(4-fluorophenyl)-6-[[(2-hydroxy- 1, 2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]- N-methyl-5-(1 -methylethyl)- 1-benzofuran-3-carboxamide

A mixture of 2-(4-fluorophenyl)-/V-methyl-5-(1 -methylethyl)-6-[(methylsulfonyl)(2- {[(phenylmethyl)oxy]methyl}-2-propen-1 -yl)amino]-1 -benzofuran-3-carboxamide (620 mg), [lr(COD)CI]₂ (74 mg), dppe (87 mg) and THF (25 mL) was cooled to 0°C under an

atmosphere of nitrogen. HBPIN (1 .40g) was added and the mixture was maintained with stirring at ambient temperature for 48 hours. The mixture was filtered through celite and the filtrates were partitioned between ethyl acetate and water and stirred for 5 minutes. The organic layer was washed with water and brine, separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by prep-hplc to give an intermediate white solid (440 mg). LCMS {m/z, ES⁺) = 693 (M+1 ). The solids were dissolved in ethyl acetate (10 mL) and stired with Pd/C (100 mg) under 0.4 MPa of hydrogen for 48 hours. The mixture was filtered through celite and the filtrates were concentrated under reduced pressure and purified by prep-hplc to afford 2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2- oxaborolan-4-yl)methyl](methylsulfonyl)amino]-/\/-methyl-5-(1 -methylethyl )-1 -benzofu ran-3- carboxamide (7 mg, 5% Yield) as a white solid. ¹ H NMR (300 MHz, MeOD) 57.93(m, 2H), 7.70 (m, 2H), 7.27 (m, 2H), 3.69 (m, 4H),3.06 (m, 3H),2.98 (m, 3H), 2.04(m, 2H), 1.30(m, 6H), 0.93(m, 2H). LCMS {m/z, ES⁺) = 503 (M+1 ). Two exchangeable protons not evident.

Example 16

2-(4-fluorophenyl)-6-rr(2-hvdroxy-1 ,2-oxaborolan-4-yl)methyll(methylsulfonyl)aminol-/\/,5- dimethyl-1-benzofuran-3-carboxamide

Step 1: ethyl 2-(4-fluorophenyl)-5-methyl-6-nitro-1-benzofuran-3-carboxylate

A solution of ethyl 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1- benzofuran-3-carboxylate (2.86g, 6 mmol), KF (1.15 g, 30 mmol), NaBr (614 mg, 12 mmol), methylboronic acid (538 mg, 9 mmol), and Pd(PPh₃)₄ (345 mg, 0.3 mmol) in toluene (30 mL) and water was evacuated for 3 minutes and then purged with nitrogen. The mixture was refluxed under nitrogen for 24 hours, cooled to ambient temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and triturated with diethyl ether to afford ethyl 2-(4-fluorophenyl)-5-methyl-6-nitro-1 -benzofuran-3-carboxylate as a yellow solid (2.2g, quant. Yield). LCMS {m/z, ES⁺) = 344 (M+1 ). Step 2: ethyl 6-amino-2-(4-fluorophenyl)-5-methyl-1-benzofuran-3-carboxylate

A solution of ethyl 2-(4-fluorophenyl)-5-methyl-6-nitro-1 -benzofuran-3-carboxylate (2.2g, 6.4 mmol) in ethyl acetate (100 ml.) was stirred with palladium on carbon under an atmosphere of hydrogen at room temperature overnight. The mixture was filtered through celite and the filtrate was evaporated under vacuum. The resulting brown solids were triturated with methanol to afford ethyl 6-amino-2-(4-fluorophenyl)-5-methyl-1 -benzofuran-3- carboxylate (1 .07g, 53% Yield) as a yellow solid. LCMS {m/z, ES⁺) = 314 (M+1 ).

Step 3: 2-(4-fluorophenyl)-5-methyl-6-[(methylsulfonyl)amino]- 1-benzofuran-3-carboxylic acid

Methanesulfonyl chloride (0.573 ml_, 1 1.7 mmol) was added to a chilled solution of ethyl 6-amino-2-(4-fluorophenyl)-5-methyl-1 -benzofuran-3-carboxylate (1.05 g, 3. 4 mmol) in dichloromethane. Next DIPEA (1.46 ml.) was added the the reaction was allowed to warm to room temperature where it was maintained with stirring for one hour. The reaction was diluted with water and extracted with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography. The resulting residue was dissolved in ethanol (30 ml.) and water (15 ml.) and potassium hydroxide (4.7g, 56 mmol) was added. The resulting solution was heated to reflux for 0.5 hours and then concentrated. The solids were dissolved in water and the solution was acidified via dropwise addition of 1 N HCI. A white precipitate formed which was collected via vacuum filtration to afford 2-(4-fluorophenyl)-5-methyl-6-

[(methylsulfonyl)amino]-1-benzofuran-3-carboxylic acid (0.904g, 92% Yield) as a white solid. LCMS {m/z, ES⁺) = 364 (M+1 ).

Step 4: 2-(4-fluorophenyl)-N,5-dimethyl-6-[(methylsulfonyl)amino]-1-benzofuran-3- carboxamide

A solution of 2-(4-fluorophenyl)-5-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxylic acid (0.904 g, 2.5 mmol) in DMF (3.6 mL) and triethylamine (1 .1 mL) was treated with HATU (1.64g, 4.3 mmol) and maintained with stirring at room temperature for 1 hour. Methylamine was added (9 mL, 2M solution) and the mixture was stirred under nitrogen for 12 hours. The reaction mixture was evaporated under vacuum to give an oily liquid which was dissolved in dichloromethane and washed with 2N HCI (aq). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to a residue under reduced pressure. The residue was washed with dichloromethane to give 2-(4-fluorophenyl)- /V,5-dimethyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (0.52g, 56% Yield) as a pale yellow solid. LCMS {m/z, ES⁺) = 377 (M+1 ). Step 5: 2-(4-fluorophenyl)-N, 5-dimethyl-6-[(methylsulfonyl)(2-{[(phenylmethyl)oxy]methyl}-2- propen-1-yl)amino]-1-benzofuran-3-carboxamide

Potassium carbonate (570 mg, 2.4 mmol) and ({[2-(bromomethyl)-2-propen-1 - yl]oxy}methyl)benzene (570 mg, 2.4 mmol) were added to a solution of 2-(4-fluorophenyl)- A/,5-dimethyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (400 mg, 1 .06 mmol) in acetonitrile (5.5 ml_). The mixture was heated to reflux and maintained with stirring overnight. The reaction was cooled, diluted with water, and extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, concentrated to a residue under reduced pressure, and purified by column chromatography to give 2-(4-fluorophenyl)- A/,5-dimethyl-6-[(methylsulfonyl)(2-{[(phenylmethyl)oxy]methyl}-2-propen-1-yl)amino]-1 - benzofuran-3-carboxamide (435 mg, 76% Yield) as a white foam. LCMS {m/z, ES⁺) = 537 (M+1 ).

Step 6: 2-(4-fluorophenyl)-6-[[(2-hydroxy- 1, 2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]- N,5-dimethyl-1-benzofuran-3-carboxamide

A solution of 2-(4-fluorophenyl)-/V,5-dimethyl-6-[(methylsulfonyl)(2-

{[(phenylmethyl)oxy]methyl}-2-propen-1 -yl)amino]-1 -benzofuran-3-carboxamide (435 mg, 0.8 mmol), [lr(COD)CI]₂ (55 mg), and dppe (64 mg) in anhydrous tetrahydrofuran was cooled to 0°C under a nitrogen atmosphere and then treated with HBPIN (1.04g). Molecular sieves were added and the mixture was stirred at ambient temperature for 18 hours. The mixture was filtered through celite and the filtrates were partitioned between ethyl acetate and water and stirred for 5 minutes. The organic phase was washed with water and brine and the organic layer was separated, dried over sodium sulfate, filtered, concentrated to a residue under reduced pressure, and purified by column chromatography to afford a clear oil. The oil was dissolved in ethyl acetate and stirred with palladium on carbon (1 10 mg) under 0.4 MPa of hydrogen for 66 hours. The mixture was filtered through celite and the filtrate was evaporated under vacuum to give a white solid which was purified by prep-HPLC to afford 2- (4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]-/\/,5- dimethyl-1-benzofuran-3-carboxamide (50 mg, 32% Yield) as a white solid. ¹ H NMR (300 MHz, MeOD) δ: 7.96(m, 2H), 7.36 (m, 2H), 7.26 (m, 2H), 3.69 (m, 4H),3.05 (m, 3H),2.98 (m, 3H), 2.53(m, 3H), 2.05(m, 1 H), 0.93(m, 2H). LCMS {m/z, ES⁺) = 475 (M+1 ). Two exchangeable protons not evident. Example 17

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborinan-4- l)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: 4-(benzyloxy)butanal

A solution of 4-(benzyloxy)butan-1-ol (10 g, 55.5 mmol) in anhydrous DCM (50ml_) at 0 °C was treated with PCC (17.94 g, 83.2 mmol) and the mixture was stirred for 45 mins. The mixture was allowed warm to 25 °C and stirred for 3 h. The suspension was filtered through celite, concentrated, and purified by column chromatography to give 4-(benzyloxy)butanal (9.5 g, 96% yeild).

Step 2: 4-(benzyloxy)-2-methylenebutanal

A solution of 4-(benzyloxy)butanal (9.5g 53.3 mmol) in H₂0 (40 mL) under argen was added dimethylamine (3.61 mL, 27.6 mmol), AcOH(3.4 mL, 55.3 mmol) and aqueous (36%) formaldehyde (4.31 mL, 55.3 mmol) and heated to reflux for 1 h. The reaction mixture was poured to ice/H₂0 and extracted with EtOAc (2x100 mL). The combined organic layer was washed sequentially with 1 N NaHC0₃, H₂0 and brine, dried and concentrated to afford the crude 4-(benzyloxy)-2-methylenebutanal (9 g, 89% yield). The crude product was used without further purification.

Step 3: 4-(benzyloxy)-2-methylenebutan-1-ol

A solution of 4-(benzyloxy)-2-methylenebutanal (9 g, 47.4 mmol) in MeOH (150 mL) under N₂ atmosphere was cooled to 0 °C, NaBH₄ (2.7 g, 71 mmol) was added and the solution was stirred overnight. The reaction mixture was evaporated and poured into ice/water, extracted with EtOAc (3x200 mL). The organic extracts were washed with H₂0 and brine, dried and concentrated. The crude product was purified by column chromatography to afford 4-(benzyloxy)-2-methylenebutan-1 -ol (1.8g, 17.8% yield, two steps)

Step 4: ((3-(bromomethyl)but-3-enyloxy)methyl)benzene

A solution of 4-(benzyloxy)-2-methylenebutan-1 -ol (1.78 g, 9.3 mmol) in DCM(100 mL) was added PPh₃ (4.85 g, 18.6 mmol) and NBS (3.30 g, 18.6 mmol) and the solution was stirred for 5 mins. Then the reaction mixture was poured into saturated aqueous sodium bicarbonate, extracted with DCM (3x100 mL). The organic extracts were dried over anhydrous Na₂S0₄ and concentrated. The crude product was purified with column chromatography to afford ((3-(bromomethyl)but-3-enyloxy)methyl)benzene (1 .45 g, 61 % yield) Step 5: 6-(N-(4-(benzyloxy)-2-methylenebutyl)methylsulfonamido)-5-cyclop

fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (300 mg; 0.745 mmol) and potassium carbonate (309 mg; 2.24 mmol) in dry acetontitrile (10 ml.) was treated with ((3- (bromomethyl)but-3-enyloxy)methyl)benzene (419 mg; 1 .65 mmol) and the reaction stirred at reflux under nitrogen for 6 hour. The reaction was allowed to cool then diluted with water (30 ml.) and extracted three times with dichloromethane (100 ml. total). The combined organic solutions were dried using anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to give 6-(N- (4-(benzyloxy)-2-methylenebutyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide, 400 mg, 93% yield. LCMS {m/z, ES⁺) = 599 (M+Na)

Step 6: 6-(N-(4-(benzyloxy)-2-((4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)methyl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzo carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (48mg, 0.069 mmol)and 6-(N-(4- (benzyloxy)-2-methylenebutyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (400 mg, 0.694 mmol) were dissolved in THF (10 ml.) under a nitrogen atromsphere. Pinacolborane (1.01 ml_, 6.94 mmol) was added and the mixture stirred for 3 h. The solvent was removed in vacuo and the crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to give 6-(N-(4- (benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl)butyl)methylsulfonamido)- 5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .1 g, 225% yield). Step 7: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborinan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(4-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide was dissolved (395 mg, 0.685 mmol) in THF (10 ml_). 395 mg of Pd/C (10%) was added and stirred under H₂ (60 Psi) at room tempurature for 6 h. The mixture was filtered and concentrated. The crude product was purified by pre-HPLC to give 5-cyclopropyl-2-(4- fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborinan-4-yl)methyl)methylsulfonamido)-N- methylbenzofuran-3-carboxamide. (65mg, 22.6% yield). ¹ H NMR(300 MHz, CDCI3) δ = 7.89- 7.83 (m, 2H), 7.48 (s, 1 H), 7.28-7.16 (m, 3H), 5.75 (s, 1 H), 4.4-4.1 1 (m, 1 H), 3.92-3.82 (m, 1 H), 3.74-3.52 (m, 2H), 3.00-2.98 (m, 6H), 2.41 -2.27 (m, 1 H), 2.03-1.36 (m, 4H), 1.13-0.96 (m, 3H), 0.77-0.50 (m, 2H); LCMS (m/z) ES+ = 515 (M+1 ). One exchangeable proton not evident.

Example 18

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hvdroxy-1 ,2-oxaborolan-4- yl)ethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: ((2-methylallyloxy)methyl)benzene

2-methylprop-2-en-1-ol (7.5 g, 104 mmol) was added to a solution of NaH (3.93 g, 1 14.4 mmol) in dry THF (50 mL) at 0 °C under N₂ atmosphere and the mixture was stirred for 30 mins at this temperature, then benzyl bromide (12.4 mL, 104 mmol) in dry THF (50 mL) was added and stirred for 5 h. The reaction was quenched with H₂0 (50 mL), THF was removed under reduced pressure. The mixture was extracted with EA (3x200 mL), the organic extracts were washed with 1 N HCI (2^*100 mL), dried and concentrated to give the crude ((2-methylallyloxy)methyl)benzene (16.87, 100% yield). Step 2: 3-(benzyloxymethyl)but-3-en-1-ol

To a stirred solution of 3-(benzyloxymethyl)but-3-en-1-ol (16.87 g, 104 mmol), paraformaldehyde (3.1 g, 104 mmol) and dry dichloromethane (240 mL) in the presence of MS 4A was added dimethylaluminum chloride (1 15.6 mL of 0.9 M solution in hexane, 104 mmol) at -78 °C. The reaction temperature was gradually raised to room temperature, and the mixture was stirred for 10 h. To the reaction mixture was then added a saturated aqueous solution of sodium sulfate and MTBE. After 12 h, to the mixture was added anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ether :2:1 ) to afford 3-(benzyloxymethyl)but- 3-en-1-ol (2.3 g, 1 1 .5%).

Step 3: ((4-bromo-2-methylenebutoxy)methyl)benzene A solution of 3-(benzyloxymethyl)but-3-en-1-ol (2.2 g, 1 1 .4 mmol) in DCM (200 mL) was added PPh₃ (3.6 g, 13.68 mmol) and CBr₄ (6.8 g, 20.52 mmol) and stirred for 5 h. Then the reaction mixture was washed with saturated aqueous sodium bicarbonate (3^*100 ml). The organic layer was separated, dried over anhydrous Na₂S0₄ and concentrated. The crude product was purified with column chromatography to afford ((4-bromo-2- methylenebutoxy)methyl)benzene (1.7 g, 58% yield).

Step 4: 6-(N-(3-(benzyloxymethyl)but-3-enyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (250 mg; 0.622 mmol) and potassium carbonate (257 mg; 1.87mmol) in dry acetontitrile (10 mL) was treated with ((4-bromo-2- methylenebutoxy)methyl)benzene (349 mg; 1.37 mmol) and the reaction stirred at reflux under nitrogen for 6 hour. The reaction was allowed to cool then diluted with water (30 mL) and extracted three times with dichloromethane (100 mLI total). The combined organic solutions were dried using anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to give 6-(N- (3-(benzyloxymethyl)but-3-enyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (251 mg, 70% yield).

Step 5:

6-(N-(4-(benzyloxy)-3-((4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)methyl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluo

carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (30mg, 0.0435 mmol) and 6-(N-

(3-(benzyloxymethyl)but-3-enyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (251 mg, 0.435 mmol) were dissolved in THF (10 mL) under a nitrogen atromsphere. Pinacolborane (0.635 mL, 4.35 mmol) was added and the mixture stirred for 5 h. The solvent was removed in vacuo and the crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to give 6-(N-(4-

(benzyloxy)-3-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl)butyl)methylsulfonamido)- 5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (215 mg, 70% yield).

Step 6:

5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hydroxy-1,2-oxaborolan-4- yl)ethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide 6-(N-(4-(benzyloxy)-3-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl benzofuran-3- carboxamide (215 mg, 0.305 mmol) in EA (10 mL) was treate with Pd/C(10%, 215 mg) and stirred under H₂ (60 Psi) at room temperature for 6 h. The mixture was filtered and concentrated. The crude product was purified by pre-HPLC to give 5-cyclopropyl-2-(4- fluorophenyl)-6-(N-(2-(2-hydroxy-1 ,2-oxaborolan-4-yl)ethyl)methylsulfonamido)-N- methylbenzofuran-3-carboxamide (14.5 mg, 10% yield). ¹ H NMR (300MHz, CD₃OD) δ 7.96- 7.98 (m, 2H), 7.74 (s, 1 H), 7.29-7.34 (m, 2H), 7.22 (s, 1 H), 4.04 (m, 1 H), 3.77-3.85 (m, 2H), 3.56 (m, 1 H), 3.15 (s, 3H), 3.01 (s, 3H), 2.48 (m, 1 H), 2.28 (m, 1 H), 1 .36-1.67 (m, 2H), 0.97- 1.14 (m, 4H), 0.73-0.57 (m, 2H). LCMS {m/z, ES⁺) = 515 (M+1 ). Two exchangeable protons not evident.

Example 19

5-cvclopropyl-2-(4-fluorophenyl)-6-rr(2-hvdroxy-1 ,2-oxaborinan-5-yl)methyll

(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

Step 1: Hydroxymethyltributyltin

To a stirred solution of diisopropylamine (0.80 ml, 5.75 mmol) in THF (25 ml) at 0°C was added n-BuLi (3.50 ml, 5.5mmol, 1.57 M in hexanes). The solution was stirred for 30 minutes at 0°C, then tributyltin hydride (1 .33 ml, 5.0 mmol) was added dropwise and the resultant mixture was allowed to stir for a further 20 minutes. Paraformaldehyde (0.210 g, 7.0 mmol) was added. The reaction mixture was then warmed to room temperature, stirred for an additional 3 hours, and poured into Et₂0/H₂0. The organic phase was separated, the aqueous layer extracted once with Et₂0, and the combined organics were washed with H₂0 (5 ml) and brine (5 ml) and dried (Na₂S0₄). Removal of the solvent and flash chromatography gave hydroxymethyltributyltin (1 .324 g, 82% yield).

Step 2: lodomet yltributyltin

To a stirred solution of PPh₃ (1 .27 g, 4.86 mmol) in THF (10 ml) was added dropwise N-iodosuccinimide (1 .00 g, 4.86 mmol) in THF (10 ml). The solution was stirred for 10 minutes. Hydroxymethyltributyltin (1 .05 g, 3.25 mmol) in THF (10 ml) was added and the resultant mixture was stirred for an additional 16 hours. The reaction mixture was poured into pentane/H₂0, and the organics were separated, dried (Na₂S0₄) and concentrated. Flash chromatography gave iodomethyltributyltin (975 mg, 70% yield) as colorless oil.

Step 3: (Z)-4-(benzyloxy)but-2-en-1-ol

To a suspension of NaH (5.44 g, 1 13.6 mmol) in DMF (100 ml) was added (Z)-but-2- ene-1 ,4-diol (10 g, 136.1 mmol) in DMF (50 ml). Bromomethyl-benzene (29 g, 170.4 mmol) was added in DMF (50 ml) at 0°C, the mixture was stirred at room temperature for 2 hours, quenched with water (500 ml), and extracted with Et₂0 (500 ml ^*3). The organic layers were combined, dried (Na₂S0₄), concentrated, and purified by flash chromatography to afford (Z)- 4-(benzyloxy)but-2-en-1 -ol (1.1 g, 95% yield)

Step 4: (Z)-((4-(benzyloxy)but-2-enyloxy)methyl)tributylstannane

To a suspension of NaH (22.8 mg, 0.95 mmol) in THF (3 ml) was added (Z)-4- (benzyloxy)but-2-en-1 -ol (164 mg, 0.95mmol) in THF (2 ml). After HMPA (449 mg, 1 .04 mmol) was added at 0°C, the mixture was stirred at room temperature for 12 hours, quenched with water (50 ml), and extracted with Et₂0 (50 ml ^*3). The organic layers were combined, dried (Na₂S0₄), and concentrated. Flash chromatography afforded (Z)-((4- (benzyloxy)but-2-enyloxy)methyl)tributylstannane (1 16 mg 20% yield) Step 5: 2-(benzyloxymethyl)but-3-en-1-ol

n-BuLi (3.5 ml, 5.59 mmol) was added slowly to a solution of (Z)-((4-(benzyloxy)but-2- enyloxy)methyl)tributylstannane (2.2 g,4.7 mmol) in THF (100 ml) at -78°C under nitrogen.

The mixture was stirred at -78°C for 4 hours before being quenched with water (100 ml). The layers were separated and extracted with Et₂0 (100 ml ^*3). The organic layers were combined and washed with water (50 ml^*3), dried (Na₂S0₄) and concentrated. Flash chromatography afforded 2-(benzyloxymethyl)but-3-en-1-ol (1.1 g 95% yield).

Step 6: ((2-(bromomethyl)but-3-enyloxy)methyl)benzene

To a stirred solution of PPh₃ (1 .07 g, 4.09 mmol) in THF (30 ml) was added dropwise N-bromopyrrolidine (588 mg,3.44 mmol) in THF (30 ml). The solution was stirred for 10 minutes, and 2-(benzyloxymethyl)but-3-en-1 -ol (330 mg, 1.72 mmol) was added. Additional THF (30 ml) was added and the resultant mixture was stirred for an additional 2 hours. The reaction mixture was poured into Et₂0/H₂0 (100 ml), and the organics were separated, dried (Na₂S0₄), and concentrated. Flash chromatography afforded ((2-(bromomethyl)but-3- enyloxy) methyl)benzene (196 mg, 45% yield) as a colorless oil. Step 7: 6-(N-(2-(benzyloxymethyl)but-3-enyl)methylsulfonamido)-5-cyclopropyl- 2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxamide (166 mg; 1.2 mmol) were added to dry DMF (10 ml.) and treated with ((2- (bromomethyl)but-3-enyloxy)methyl)benzene (100 mg; 0.400 mmol). The reaction was stirred at 80 °C under nitrogen for 48 hours. The reaction was allowed to cool, diluted with water, (10 ml.) and extracted three times with dichloromethane (150ml_ total). The combined organic solutions were dried using anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography to afford 6-(N-(2-(benzyloxymethyl)but-3- enyl)methylsulfonamido)-5-cyclopropyl- 2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (45 mg, 20% yield). LCMS {m/z, ES⁺) = 577 (M+H)

Step 8: 6-(N-(2-(benzyloxymethyl)-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl) butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (7mg, 0.01 mmol) and 6-(N-(2- (benzyloxymethyl)but-3-enyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluoro phenyl)-N- methylbenzofuran-3-carboxamide (45 mg, 0.08 mmol) were dissolved in THF (10 ml.) under a nitrogen atmosphere. HBPIN (102 mg, 0.80 mmol) was added and the mixture was stirred for 3 hours. The solvent was removed in vacuo and the crude product was purified by column chromatography to give crude 6-(N-(2-(benzyloxymethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide used directly in the next step without further purification. Step 9: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborinan-5-yl)

methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Crude 6-(N-(2-(benzyloxymethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide was dissolved (from above) in THF (10 ml.) and treated with 195 mg of Pd/C (10%) and stirred under H₂ (60 PSI) at room tempurature for 6 h. The mixture was filtered and concentrated. The crude product was purified by HPLC to give 5-cyclopropyl-2-(4- fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborinan-5-yl)methyl] (methylsulfonyl)amino]-/\/-methyl-1 - benzofuran-3-carboxamide. (9 mg, 22.6% yield) LCMS {m/z, ES⁺) = 515 (M+1 ). H1-NMR (300MHz, CD₃OD) d 7.96 (t, J=5.1 Hz, 2H), 7.76 (d, J=8.4Hz, 1 H), 7.29 (t, J=8.7Hz, 1 H), 7.17 (d, J=5.4Hz, 2H), 3.79-3.37 (m, 5H), 3.09 (s, 3H), 2.51 (m, 1 H), 1 .74 (m, 1 H), 1 .31-0.90 (m, 7H), 0.71 (m, 2H). One exchangeable proton not observed. Example 20

5-cvclopropyl-2-(4-fluorophenyl)-6-[[2-(2-hydroxy-1 ,2-oxaborolan-5- yl)ethyll(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

Step 1: Ethyl 3-hydroxypent-4-enoate

n-BuLi (41 ml, 103 mmol) was added slowly to a solution of diisopropylamine (10.4 g, 103 mmol) in THF(500 ml) at 0°C, stirred for 15 minutes, cooled to -78°C, and distilled EtOAc (10.2 g, 1 16 mmol) was added slowly. Stirring was continued for an additional hour.

Acrylaldehyde (5 g, 89 mmol) was added and stirring maintained for 30 minutes before being quenched with water (200ml). The layers were seperated and the mixture was extracted with Et₂O(400 ml ^*3). The combined organic layers were dried with Na₂S0₄ and concentrated under vacuum to provide ethyl 3-hydroxypent-4-enoate as a yellow oil (6.5 g, 51 % yield)

Step 2: Ethyl 3-(tert-butyldimethylsilyloxy)pent-4-enoate

To a solution of ethyl 3-hydroxypent-4-enoate(100 mg, 0.69 mmol) in THF(10 ml) was added imidazole (95.2 mg, 1.38 mmol) at room temperature. TBSCI (156 mg, 1 .04 mmol) was added and stirring was maintained for 2 hours. The mixture was quenched with water (10 ml), extracted with ethyl acetate (15 ml x3), and the organic layers were combined, dried over Na₂S0₄, concentrated under vacuum, and purified by column chromatography to give ethyl 3- (tert-butyldimethylsilyloxy)pent-4-enoate (138 mg, 74 % yield).

Step 3: 3-(tert-butyldimethylsilyloxy)pent-4-en-1-ol

A suspension of lithium aluminum hydride (17.1 mg, 0.45 mmol) in dry DCM(10 ml) was stirred at room temperature and a THF solution of ethyl 3-(tert- butyldimethylsilyloxy)pent-4-enoate (100 mg, 0.38 mmol) was added dropwise. The reaction was allowed to reflux for 3 hours and quenched with water (10 ml ). The reaction mixture was extracted with EtOAc(15 ml x 3). The organic layer was washed with water (30 ml), dried with Na₂S0₄, concentrated under vacuum, and purified by column chromatography to afford 3- (tert-butyldimethylsilyloxy)pent-4-en-1-ol (85 mg, 96 % yield).

Step 4: {[1-(2-bromoethyl)-2-propen-1 -yl]oxy}(1 , 1-dimethylethyl)dimethylsilane To a mixture of 3-(tert-butyldimethylsilyloxy)pent-4-en-1-ol (85 mg),

triphenylphosphine (306 mg, 1 .17 mmol ), and dry dichloromethane (10 ml) cooled in an ice bath was added N-bromosuccinimide (138 mg,0.78 mmol) in several portions with vigorous stirring. Stirring was continued for 3 hours at room tempreture, then hexane (50 ml) was added to the flask, and the mixture was purified by silica gel chromatography to afford {[1-(2- bromoethyl)-2-propen-1-yl]oxy}(1 , 1 -dimethylethyl) dimethylsilane (50 mg, 40 % yield).

Step 5: 6-(N-(3-(tert-butyldimethylsilyloxy)pent-4-enyl)methylsulfonamido)-5- cyclopropyl-2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxamide (360 mg; 0.9 mmol) and potassium carbonate (370 mg; 2.7 mmol) was added to dry DMF (15 mL) and treated with {[1-(2-bromoethyl)-2-propen-1 -yl]oxy}(1 , 1- dimethylethyl)dimethylsilane (250 mg; 0.9 mmol). The reaction was stirred at 60 °C under nitrogen for 12 hours. The reaction was allowed to cool then diluted with water (10 mL) and extracted three times with dichloromethane (200 mL total). The combined organic layers were dried using anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography to afford 6-(N-(3-(tert-butyldimethylsilyloxy)pent-4-enyl)

methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (281 mg, 52% yield . LCMS {m/z, ES⁺) = 601 (M+H)

Step 6: 6-(N-(3-(tert-butyldimethylsilyloxy)-5-(4^,5,5-tetrame dioxaborolan-2- yl)pentyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophen

carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (34mg, 0.05 mmol) and 6-(N-(3- (tert-butyldimethylsilyloxy)pent-4-enyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)- N-methylbenzofuran-3-carboxamide (281 mg, 0.47 mmol) were dissolved in THF (20 mL) under a nitrogen atmosphere. HBPIN (601 mg, 4.7 mmol) was added and the mixture was stirred for 3 hours. The solvent was removed in vacuo and the crude product was purified by column chromatography to afford 6-(N-(3-(tert-butyldimethylsilyloxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)pentyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (170 mg, 50% yield).

Step 7: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hydroxy- 1, 2-oxaborolan-5- yl)ethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(3-(tert-butyldimethylsilyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pentyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (170 mg,0.23 mmol) was dissolved in absolute ethanol (15 ml) and PPTS (58 mg, 0.23 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 12h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with saturated aqueous brine, washed with water, and then dried over MgS0₄. The solvent was evaporated in vacuo and the crude product was purified by HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-[[2-(2-hydroxy-1 ,2- oxaborolan-5-yl)ethyl](methylsulfonyl)amino]-/\/-methyl-1-benzofuran-3-carboxamide (20 mg, 17% yield) LCMS {m/z, ES⁺) = 515 (M+1 ). H1-NMR (300MHz, CD₃OD) d 8.46 (s, 1 H), 7.99- 7.94 (dd, J=2.1 Hz, 2H), 7.74 (d, J=4.2Hz, 1 H), 7.32-7.27 (dd, J=2.1 Hz, 2H), 7.22 (d, J=3.3Hz, 1 H), 4.13 (m, 1 H), 4.1 1-3.83 (m, 2H), 3.16 (s, 3H), 3.04 (s, 3H), 2.47 (m, 1 H), 2.08 (m, 1 H), 1 .78-1.50 (m, 4H), 1 .03-0.71 (m, 5H). One exchangeable proton not observed.

Example 21

r({(2f?)-3-r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminol-2-methylpropyl}oxy)methyllboronic acid

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsu

(tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (10 mg, 0.025 mmol), 2-{[(2S)-3-bromo-2- methylpropyl]oxy}tetrahydro-2H-pyran {Organic Letters, 2005, 7(13) p. 2599-2602), (18 mg, 0.075 mmol), TBAI (9 mg, 0.025 mmol), and potassium t-butoxide (3 mg, 0.0275 mmol) in tetrahydrofuran (1 ml.) was maintained at 50°C for 10 minutes in a microwave reactor followed by heating for a total of 30 minutes at 100 °C in a microwave reactor. The tetrahydrofuran was removed under reduced pressure and the mixture diluted with water and dichloromethane. The organic layer was dried over sodium sulfate and purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-{(methylsulfonyl)[(2R)- 2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1 -benzofuran-3-carboxamide (4 mg, 32% yield). Step 2: 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2R)-3-hydroxy-2- methylpropyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-{(methylsulfonyl)[(2R)-2- methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1 -benzofuran-3-carboxamide (80 mg, 0.14 mmol) in tetrahydrofuran was treated with 4. ON HCI (1 ml.) and maintained with stirring for 24 hours at room temperature. The mixture was diluted with diethyl ether and the organic layer was washed with brine, separated, and dried over sodium sulfate. The solvent was removed under vacuum and the residue purified by column chromatography to afford 5- cyclopropyl-2-(4-fluorophenyl)-6-[[(2R)-3-hydroxy-2-methylpropyl](methylsulfonyl)amino]-/\/- methyl-1 -benzofuran-3-carboxamide.

Step 3: [({(2R)-3-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofura 6-yl}(methylsulfonyl)amino]-2-methylpropyl}oxy)methyl]boronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2R)-3-hydroxy-2- methylpropyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (39 mg, 0.082 mmol), 2-(bromomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (45.4 mg, 0.205 mmol), and potassium carbonate (34.1 mg, 0.247 mmol) in acetonitrile (5 ml.) was maintained at 80 °C for 12 hours. The mixture was diluted with dichloromethane, filtered through celite, concentrated, and purified by reverse phase hplc to afford [({(2R)-3-[{5-cyclopropyl-2-(4- fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]-2- methylpropyl}oxy)methyl]boronic acid (18 mg, 0.034 mmol, 41.1 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.91 (dd, J = 8.9, 5.4 Hz, 2H), 7.72 (d, J = 13.7 Hz, 1 H), 7.24 (t, J = 8.7 Hz, 2H), 7.12 (s, 1 H), 3.76 - 3.92 (m, 1 H), 3.60 (dd, J = 13.7, 7.2 Hz, 1 H), 3.15 (d, J = 12.7 Hz, 1 H), 3.06 (d, J = 1.6 Hz, 3H), 2.93 (s, 3H), 2.41 - 2.56 (m, 4H), 1 .78 - 1 .95 (m, 1 H), 0.84 - 1.14 (m, 6H), 0.59 - 0.74 (m, 1 H). LCMS {m/z, ES⁺) = 533 (M+H)

Example 22

r({(2S)-3-r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminol-2-methylpropyl}oxy)methyllboronic acid

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsulfonyl)[(2S)-2-methyl-3- (tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (230 mg, 0.57 mmol), 2-{[(2R)-3-bromo-2- methylpropyl]oxy}tetrahydro-2H-pyran {Tetrahedron Letters. 1986, 27(28) p. 331 1.), (403 mg, 1.71 1 mmol), potassium tert-butoxide (71 mg, 0.63 mmol), and TBAI (210 mg, 0.57 mmol) in tetrahydrofuran (5 ml.) was maintained at 100 °C for 40 minutes in a microwave reactor. Ammonium chloride solution (aqueous) was added and the aqueous layer was extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-6-{(methylsulfonyl)[(2S)-2-methyl-3-(tetrahydro-2/-/-pyran-2- yloxy)propyl]amino}-1-benzofuran-3-carboxamide as a white solid (150 mg, 67% yield).

Step 2: 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2S)-3-hydroxy-2- methylpropyl](methylsulfonyl)amino]-N-methyl- 1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-{(methylsulfonyl)[(2S)-2- methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1 -benzofuran-3-carboxamide (200 mg, 0.36 mmol) in tetrahydrofuran (2 ml.) was treated with 4. ON HCI (0.4 ml.) and maintained with stirring at room temperature for 24 hours. Ethyl acetate was added and the organic layer was washed with brine, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 5-cyclopropyl-2-(4- fluorophenyl)-6-[[(2S)-3-hydroxy-2-methylpropyl](methylsulfonyl)amino]-/\/-methyl-1- benzofuran-3-carboxamide as a white solid (97 mg, 57% yield). Step 3: [({(2S)-3-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]-2-methylpropyl}oxy)methyl]boronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2S)-3-hydroxy-2- methylpropyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (43.1 mg, 0.091 mmol), 2-(bromomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (50.2 mg, 0.227 mmol), and potassium carbonate (38 mg, 0.247 mmol) in acetonitrile (5 ml.) was maintained at 80°C for 12 hours. The mixture was diluted with dichloromethane, filtered through celite,

concentrated, and purified by reverse phase hplc to afford [({(2S)-3-[{5-cyclopropyl-2-(4- fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]-2- methylpropyl}oxy)methyl]boronic acid (16 mg, 0.030 mmol, 33.1 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.91 (dd, J = 8.9, 5.4 Hz, 2H), 7.72 (d, J = 13.7 Hz, 1 H), 7.24 (t, J = 8.7 Hz, 2H), 7.12 (s, 1 H), 3.76 - 3.92 (m, 1 H), 3.60 (dd, J = 13.7, 7.2 Hz, 1 H), 3.15 (d, J = 12.7 Hz, 1 H), 3.06 (d, J = 1.6 Hz, 3H), 2.93 (s, 3H), 2.41 - 2.56 (m, 4H), 1 .78 - 1 .95 (m, 1 H), 0.84 - 1.14 (m, 6H), 0.59 - 0.74 (m, 1 H). LCMS {m/z, ES⁺) = 533 (M+H)

Example 23

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: ((1-bromobut-3-en-2-yloxy)methyl) benzene

To a solution of 1-bromobut-3-en-2-ol (50 mg, 0.33 mmol) in 1 mL of Et₂0, benzyl 2,2,2-trichloroacetimidate (336 mg, 1 .33 mmol) in 2 mL of Et₂0 was added at N₂ atmosphere, and then trifluoromethanesulfonic acid (50 mg, 0.33 mmol) in 2 mL of Et₂0 was added at 0 °C. The resultant mixture was stirred overnight at room temperature. The reaction mixture was poured into saturated NaHC0₃ solution (5 mL), the organic layer was separated, washed with brine (5 mL), dried over Na₂S0₄, and concentrated in vacuo. The residue was purified by column chromatography (eluting with PE ) to give ((1-bromobut-3-en-2- yloxy)methyl)benzene (59 mg, 74% yield) .

Step 2: 6-(N-(2-(benzyloxy)but-3-enyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido) benzofuran-3-carboxamide (20 mg 0.05 mmol) and potassium carbonate (21 mg, 0.15 mmol) in 2 mL of dry DMF was treated with ((1-bromobut-3-en-2-yloxy)methyl)

benzene (24 mg, 0.1 mmol) and the reaction mixture was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(2-(benzyloxy)but-3-enyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (16 mg, 56% yield) . LCMS (m/z, ES⁺) = 563 (M+1 )⁺

Step 3: 6-((2-(benzyloxy)-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)butyl) (hydrosulfonyl)amino)-5-cyclopropyl-2-(4-fluorop

Carbonylbis(triphenylphosphine)rhodium(l) chloride (50 mg, 0.073 mmol) and 6-(N-(2- (benzyloxy)but-3-enyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (410 mg, 0.73 mmol) were dissolved in THF (15 mL) under a nitrogen atmosphere. Pinacolborane (467 mg, 3.65 mmol) was added and the mixture stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6- ((2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-

2-yl)butyl)(hydrosulfonyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (407 mg, 81 % yield).

Step 4:5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborolan-5-yl)

methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-((2-(Benzyloxy)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)butyl)(hydrosulfonyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (407 mg, 0.59 mmol) was dissloved in 10 mL of THF, and then 407 mg of Pd/C (10%) was added and stirred under H₂ (60 PSI) at room tempurature for 6 h. The mixture was filtered and concentrated. The residue was purified by pre-HPLC to give 5-cyclopropyl- 2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-5-yl)methyl)methylsulfonamido)-N- methylbenzofuran-3-carboxamide (1 15 mg, 39% yield). ¹H NMR (300MHz, CD₃OD-d₄) δ = 7.97-7.91 (m,2H), 7.75-7.34(d, 1 H), 7.30-7.23(m,3H), 4.27(m, 1 H), 3.99-3.60 (m,3H),

3.45(m,3H), 3.12(m,3H), 2.97(s,3H), 2.54-2.36(m, 1 H), 1.96(m,1 H), 1.61 (m, 1 H), 1 .10(m,1 H), 1.07-0.65(m, 1 H). LCMS( m/z) ES⁺=501 (M+1 ) Example 24

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-isopropylbenzofuran-3-carboxamide

Step 1 : 5-Cyclopropyl-2-(4-fluorophenyl)-N-isopropyl-6-(methylsulfonamido)benzofuran-3- carboxamide

5-Cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (1 .0 g, 2.568 mmol) was stirred in 15 mL of dry DMF at ambient temperature with DIPEA (0.730 g, 5.650 mmol) and HATU (1.171 g, 3.082 mmol) were added. After stirring for 15 mines, propan-2-amine (0.608 g, 10.272 mmol) was added. The reaction mixture was stirred for another 2 hours and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL x2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0- 50%, ethyl acetate in petroleum) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-isopropyl-6- (methylsulfonamido)benzofuran-3-carboxamide (0.75 mg, 68% yield). Step 2: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluoroph N-isopropylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-isopropyl-6- (methylsulfonamido)benzofuran-3-carboxamide (750 mg, 1 .744 mmol), Kl (29 mg, 0.174 mmol) and K₂C0₃ (723 mg, 5.232 mmol) in dry DMF (10 mL) was treated with ((2- (bromomethyl)allyloxy)methyl)benzene (921 mg, 3.836 mmol) and the reaction mixture was heated to reflux under nitrogen for half an hour. The reaction mixture was cooled, diluted with water (15 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(2- (benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- isopropylbenzofuran-3-carboxamide (580 mg, 56% yield) . LCMS (m/z, ES⁺) = 591 (M+1 )⁺

Step 3: 6-(N-(3-(benzyloxy)-2-((4,4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-isopropylbenzofuran- 3-carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (68 mg, 0.0983 mmol) and 6-(N- (2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- isopropylbenzofuran-3-carboxamide (580 mg, 0.983 mmol) were dissolved in THF (10 mL) under nitrogen atmosphere. Pinacolborane (629 mg, 4.91 mmol) was added and the mixture stirred for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(3-(benzyloxy)- 2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl)propyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-isopropylbenzofuran-3-carboxamide (957 mg, 136% yield). Step 4: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-isopropylbenzofuran-3-carboxamide 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-isopropylbenzofur^ 3-carboxamide (957 mg, 0.983 mmol, crude) was dissloved in THF (10 mL), and 957 mg of Pd/C (10%) was added and stirred under H₂ (60 PSI) at room temperature for 6 h. The mixture was filtered and concentrated. The residue was dissoved in THF (10 mL) and treated with 5 N HCI (1 .4 mL) and PS-benzene boronic acid (1 .890 g, 4.915 mmol). The suspension was stirred for 4 hours, filtered, and concentrated in vacuo. The residue was purified by pre-HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2- oxaborolan-4-yl)methyl)methylsulfonamido)-N-isopropylbenzofuran-3-carboxamide (137 mg, 26% yield). 1 H NMR (300MHz, CD₃OD-d₄) δ = 7.92-7.86(m,2H), 7.47-7.45(d, 1 H),

7.33(m,1 H), 7.28-7.17(m,2H), 5.57-5.54 (d,2H), 4.42-4.31 (m, 1 H), 4.18-4.08(m, 1 H), 3.94- 3.90(m.1 H), 3.82-3.62(m,3H), 3.00(m, 1 H), 2.52-2.30(m,2H), 1 .27-0.69(m,1 1 H). LCMS( m/z) ES⁺=529(M+1 ) Example 25

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-(2-hvdroxyethyl)benzofuran-3-carboxamide

Step 1: N-(2-(benzyloxy)ethyl)-5-cyclopropyl-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxamide

5-Cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (1 .0 g, 2.568 mmol) was stirred in dry DMF (15 mL) at ambient temperature with DIPEA (0.730 g, 5.650 mmol) and HATU (1.71 g, 3.082 mmol). After stirring for 15 minutes, benzyloxymethanamine (1 .552 mg, 10.272 mmol) in 15 mL of THF was added. The reaction mixture was stirred for another 2 hours and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL x2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column

chromatography (eluting with 0-50% ethyl acetate in petroleum) to give N-(2- (benzyloxy)ethyl)-5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3- carboxamide (1.4 g, crude, 104% yield). Step 2: N-(2-(benzyloxy)ethyl)-6-(N-(2-(benzyloxymethyl)allyl)methylsulfon

cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxamide.

A suspension of N-(2-(benzyloxy)ethyl)-5-cyclopropyl-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxamide (1 .4 g, crude,2.681 mmol), Kl (45 mg, 0.268 mmol) and K₂C0₃ (1.1 1 g, 8.043 mmol) in dry DMF (10 mL) was treated with ((2-

(bromomethyl)allyloxy)methyl)benzene (1.416 g, 6.215mmol) and the reaction mixture was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (15 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give N-(2-(benzyloxy)ethyl)-6-(N-(2-

(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (1.3 g, 71 % yield). LCMS (m/z, ES⁺) = 683 (M+1 )⁺

Step 3: 6-(N-(3-(benzyloxy)-2-((4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-N-(2-(benzyloxy)ethyl)-5-cyclopropyl-2-(4- fluorophenyl)benzofuran-3-carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (132 mg, 0.191 mmol) and N-(2- (benzyloxy)ethyl)-6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)benzofuran-3-carboxamide (1.3 g, 1.91 mmol) were dissolved in THF (10 mL) under nitrogen atromsphere. Pinacolborane (1 .22 g, 9.56 mmol) was added and the mixture stirred for 3 h. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(3- (benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-N-(2-(benzyloxy)ethyl)-5-cyclopropyl-2-(4- fluorophenyl)benzofuran-3-carboxamide (1.9 g, 127% yield).

Step 4: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-( ( 2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-(2-hydroxyethyl)benzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-N-(2-(benzyloxy)ethyl)-5-cyclopropyl-2-(4- fluorophenyl)benzofuran-3-carboxamide (1 .9 g, crude, 1 .91 mmol) was dissloved in THF (10 mL). Palladium on activated carbon (1 .9g, 10% Loading) was added and stirred under H₂ (60 PSI) at room tempurature for 6 h. The mixture was filtered and concentrated. The residue was dissoved in THF (10 mL) and treated with 5 N HCI (1 .4 mL) and PS-benzene boronic acid (2.57 g, 6.69 mmol). The suspension was stirred for 4 hours, filtered, concentrated in vacuo. The crude product was purified by pre-HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)- 6-(N-((2-hydroxy-1 ,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N-(2- hydroxyethyl)benzofuran-3-carboxamide (50 mg, 5% yield). ¹H NMR (300MHz, CD30D-C/4) δ = 8.04-7.99(m,2H), 7.75-7.71 (d, 1 H), 7.30-7.24(m,3H), 3.81-3.55(m,8H),3.10 (s,3H),

2.50(m,2H), 1 .1 1-0.73(m,6H). LCMS( m/z) ES⁺=531 (M+1 ) Example 26

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4-yl)methyl)-2- methylpropylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: Ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-(2-methyl-N- (methylsulfonyl)propylsulfonamido)benzofuran-3-carboxylate

A solution of ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (1 .2 g, 3.54 mmol) in dry DCM (22 mL) at -15 °C was added TEA (1.32 mL, 8.8 mmol) under N₂ atmosphere, then added dropwise propane-2-sulfonyl chloride (1 .94 g, 12.4 mmol). The solution was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3^*20 mL). The organic layers were combined, dried with MgS0₄, filtered, and evaporated under vacuum to afford ethyl 5- cyclopropyl-2-(4-fluorophenyl)-6-(2-methyl-N-(methylsulfonyl)propylsulfonamido)benzofuran- 3-carboxylate (1 .53 g, 75 %). Step 2: 5-cyclopropyl-2-(4-fluorophenyl)-6-(2-methylpropylsulfonamido)benzofuran-3- carboxylic acid

Potassium hydroxide (2.97g, 53 mmol) was added to a solution of ethyl 5-cyclopropyl- 2-(4-fluorophenyl)-6-(2-methyl-N-(methylsulfonyl)propylsulfonamido)benzofuran-3- carboxylate (1 .5g, 3.54 mmol) in ethanol (20 mL) and water (10 mL) under nitrogen. The reaction was heated to reflux and stirred for 1 hour, then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 N HCI until a precipitate formed. The solid was filtered and dissolved in EtOAc (300 mL), dried and concerntrated to afforded 5-cyclopropyl-2-(4-fluorophenyl)-6-(2- methylpropylsulfonamido)benzofuran-3-carboxylic acid (white solid, 1 .45 g, 95 %).

Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(2- methylpropylsulfonamido)benzofuran-3-carboxamide 5-cyclopropyl-2-(4-fluorophenyl)-6-(2-methylpropylsulfonamido)benzofuran-3- carboxylic acid (1 .45g, 3.36 mmol) was dissolved in dry DMF (30 mL) at 21 °C with DIPEA (956 mg, 7.39 mmol) and HATU (1 .54 g, 4.03 mmol). After stirring for 15 minutes, 2M Methylamine (6.72 mL, 13.44 mmol) in THF was added. The solution was stirred for 2h and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution then 2M HCI (400 ml). The organics were dried using anhydrous MgS0₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatograph (EA/PE=1 :2) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(2- methylpropylsulfonamido)benzofuran-3-carboxamide (0.65 mg, 44%) as a pale white solid.

Step 4: 6-(N-(2-(benzyloxymethyl)allyl)-2-methylpropylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(2- methylpropylsulfonamido)benzofuran-3-carboxamide (0.65 g, 1 .46 mmol), Kl (12 mg, 0.07 mmol) and K₂C0₃ (0.6 g, 4.38 mmol) in dry DMF (10 mL) was treated with ((2-

(bromomethyl)allyloxy)methyl)benzene (700 mg, 2.92 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 20 minutes. The reaction was diluted with water (30 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (EA:PE = 1 :2) to give 6-(N-(2-(benzyloxymethyl)allyl)-2- methylpropylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (510 mg, 60 %).

Step 5:

6-(N-(3-(benzyloxy)-2-((4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)methyl)propyl)-2- methylpropylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (58 mg, 0.08 mmol) and 6-(N-(2- (benzyloxymethyl)allyl)-2-methylpropylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (500 mg, 0.83mmol) were dissolved in THF (20 mL) under nitrogen atromsphere. Pinacolborane (1.06 g, 8.3 mmol) was added and the mixture was stirred for 3 hrs. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to give 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl)propyl)-2- methylpropylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (crude, 780 mg, quant, yield %). Step 6: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborolan-4-yl)methyl)-2- methylpropylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl)propyl)-2- methylpropylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (780mg, 1 .06 mmol) was dissloved in THF (25 mL). 300 mg of Pd/C (10%) was added and stirred under H₂ (50 Psi) at room tempurature for 16 hours. The mixture was filtered and concentrated. The residue was dissoved in THF (25 mL) and treated with 5 N HCI (1 .49 mL) and PS-benzene boronic acid (2.05 g, 5.3 mmol). The suspension was stirred for 2 hours, filtered, and concentrated under reduced pressure. The residue was redissoved in THF (25 mL) and treated with 5 N HCI (1 .49 mL) and PS-benzene boronic acid (2.05 g, 5.3 mmol). The suspension was stirred for 2 hours, filtered, concentrated in vacuo. The crude product was purified by Prepratory-HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2- hydroxy-1 ,2-oxaborolan-4-yl)methyl)-2-methylpropylsulfonamido)-N-methylbenzofuran-3- carboxamide (95 mg, 16 %). LCMS (m/z) ES⁺ =542.9 (M+1 )

1H NMR (300 MHz, CD₃OD) δ = 7.96-7.91 (m, 2H), 7.74-7.69 (m, 1 H), 7.30-7.24 (m, 2H), 7.14 (m, 1 H), 4.10-3.61 (m, 4H), 3.19-3.14 (m, 2H), 2.97 (S, 3H), 2.52-2.43 (m, 1 H), 2.36- 2.19 (m, 2H), 1 .16-1.13 (m, 8H), 1.00-0.82 (m, 2H), 0.76-0.68 (m, 2H)

Example 27

5-cvclopropyl-N-ethyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide

Step 1: 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3- carboxamide

5-Cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (1 .0 g, 2.568 mmol) was stirred in dry DMF (15 mL) at ambient temperature and DIPEA (0.730 g, 5.650 mmol) and HATU (1.71 g, 3.082 mmol) were added. After stirring for 15 minutes, ethylamine (463 mg, 10.272 mmol) in 15 mL of THF was added. The reaction mixture was stirred for 2 hours at room temperature and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL x2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 5-cyclopropyl-N- ethyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxamide (720 mg, 67% yield).

Step 2: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-N-ethyl-2-(4- fluorophenyl)benzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxamide (720 mg, crude, 2.825 mmol), Kl (47 mg, 0.2825 mmol) and K₂C0₃ (1.17 g, 8.475 mmol) in dry DMF (10 mL) was treated with ((2- (bromomethyl)allyloxy)methyl)benzene (1.49 g, 6.215mmol) and the reaction was heated to reflux under nitrogen for half an hour. The reaction mixture was cooled, diluted with water (15 mL), and extracted with EtOAc (30 mL x3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(2-

(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-N-ethyl-2-(4- fluorophenyl)benzofuran-3-carboxamide (786 mg, 79% yield) . LCMS (m/z, ES⁺) = 577 (M+1 )⁺ Step 3: 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-N-ethyl-2-(4-fl

carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (95 mg, 0.136 mmol) and 6-(N-(2- (benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-N-ethyl-2-(4- fluorophenyl)benzofuran-3-carboxamide (786 mg, 1.364 mmol) were dissolved in THF (10 mL) under anitrogen atromsphere. Pinacolborane (873 mg, 6.82 mmol) was added and the mixture stirred for 3 h at room temperature. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (942 mg, 98% yield).

Step 4: 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (942 mg, 1 .337 mmol) was dissolved in THF (10 mL). 942 mg of Pd/C (10%) was added and stirred under H₂ (60 PSI) at room temperature for 6 h. The mixture was filtered and concentrated. The residue was dissoved in THF (10 mL) and treated with 5 N HCI (1 .4 mL) and PS-benzene boronic acid (2.57 g, 6.69 mmol). The suspension was stirred for 4 hours, filtered, concentrated in vacuo. The residue was purified by pre-HPLC to give 5- cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide (341 mg, 50% yield). 1 H NMR (300 MHz, CD₃OD-d4) δ = 7.96-7.93 (m, 2H), 7.75-7.70 (d, 1 H), 7.30-7.14 (m, 3H), 3.89-3.64(m, 4H), 3.51-3.37 (m, 2H), 3.10 (s, 3H), 2.49 (m, 1 H), 2.45 (s, 1 H), 1.28-1 .23 (m,3H), 1.47-00.69 (m, 6H). LCMS( m/z) ES⁺=515(M+1 )

Example 28

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)ethylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: Ethyl5-cyclopropyl-6-(N-(ethylsulfonyl)ethylsulfonamido)-2-(4- fluorophenyl)benzofuran-3-carboxylate

A solution of ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxylate (1 .2g, 3.5 mmol) in dry DCM (15 mL) at -15 °C under N₂ atmosphere was added TEA (1 .31 mL, 8.8 mmol), and then ethanesulfonyl chloride (1.57 g, 12.2 mmol) drop wise. The stirred solution was warmed to room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3^*20 mL). The organic layers were combined, dried over MgS0₄, filtered and evaporated under vacuum to afford ethyl 5-cyclopropyl-6-(N- (ethylsulfonyl)ethylsulfonamido)-2-(4-fluorophenyl)benzofuran-3-carboxylate 1.85 g (crude, 101 %).

Step2: 5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)benzofuran-3-carboxylic acid

Potassium hydroxide (2.48 g, 44.2 mmol) was added to a solution of ethyl 5- cyclopropyl-6-(N-(ethylsulfonyl)ethylsulfonamido)-2-(4-fluorophenyl)benzofuran-3- carboxylate(1.85g, 3.54 mmol) in ethanol (1 1 mL) and water (5.5mL) under nitrogen. The reaction mixture was heated to reflux and stirred for 1 hour, then concentrated in vacuo. The remaining solid was dissolved in water, and the solution was acidified with 1 N HCI until a precipitate formed. The solid was filtered and washed with 100 mL of mixed solvent (Et₂0/PE = 1 :1 ), then dried to afford 5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)benzofuran- 3-carboxylic acid as a white solid (1 .22 g, 87 %).

Step3: 5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide

5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)benzofuran-3-carboxylic acid (1 .22g, 3.1 mmol) was dissolved in dry N,N-Dimethylformamide (34 mL) at 21 °C with DIPEA (875 mg, 6.7 mmol) and HATU (1.41 g, 3.7 mmol). After stirring for 15 minutes, 2M methylamine in THF (6.15 mL, 12.3 mmol) was added. The solution was stirred for 2h and evaporated. The residue was dissolved in ethyl acetate (30 mL), washed with saturated sodium bicarbonate solution and 2M HCI (20 ml). The organics were dried using anhydrous MgS0₄, filtered, concentrated, and purified with column chromatograph (EA/PE = 1 :2) to give 5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.89 g, 69 %) as a pale white solid.

Step 4: 6-(N-(2-(benzyloxymethyl)allyl)ethylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (0.89 g, 2.14 mmol), Kl (18 mg, 0.1 1 mmol) and K₂C0₃ (0.89 g, 6.42 mmol) in dry DMF (15 mL) were treated with ((2-

(bromomethyl)allyloxy)methyl)benzene (1.03 g, 4.28 mmol) and the reaction stirred at room temperature under nitrogen for half an hour. The reaction was diluted with water (45 mL) and extracted with EtOAc (3^*100 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (EA:PE = 1 :2) to give 6-(N-(2-(benzyloxymethyl)allyl)ethylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (820 mg, 66 %).

Step 5: 6-(N-(3-(benzyloxy)-2-((4, 4, 5, 5-tetra methyl- 1, 3, 2-dioxaborolan-2- yl)methyl)propyl)ethylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (96mg, 0.14 mmol) and 6-(N-(2- (benzyloxymethyl)allyl)ethylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (800 mg, 1.39mmol) were dissolved in dry THF (20 mL) under a nitrogen atmosphere. Pinacolborane (1.78 mg, 13.9 mmol) was added and the mixture was stirred for 3 hours. The solvent was removed in vacuo and the crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to give 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)ethylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran carboxamide (crude, 1.65 g, 168 %). Step 6: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborolan-4- yl)methyl)ethylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)ethylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (1.65 mg, 2.34 mmol, crude) was dissolved in THF (30 mL). 660 mg of Pd/C (10%) was added and stirred under H₂ (50 PSI) at room temperature for 16 hours. The mixture was filtered and concentrated. The residue was dissolved in THF (30 mL) and treated with 5 N HCI (3.27 mL) and PS-benzene boronic acid (4.49 g, 1 1 .7 mmol). The suspension was stirred for 2 hours, filtered, and concentrated under reduced pressure. The residue was re-dissolved in THF (30 mL) and treated with 5 N HCI (3.27 mL) and PS- benzene boronic acid (4.49g, 1 1.7 mmol). The suspension was stirred for 2 hours, filtered, and concentrated under reduced pressure. The crude product was purified by pre-HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)ethylsulfonamido)-N-methylbenzofuran-3-carboxamide (105 mg, 9 %). LCMS (m/z) ES⁺ =514.9 (M+1 ). ¹H N MR (300 MHz, CD₃OD) δ = 7.97-7.95 (m, 2H), 7.73-7.69 (m, 1 H), 7.31-7.25 (m, 2H), 7.15-7.14 (m, 1 H), 4.10-3.57 (m, 4H), 3.34-3.26 (m, 2H), 2.98 (S, 3H), 2.55-2.42 (m, 1 H), 2.40-2.22 (m, 1 H), 1 .44-1.39 (m, 3H), 1.12-1.10 (m, 2H), 0.99-0.94 (m,2H), 0.78-0.69 (m, 2H).

Example 29

5-cvclopropyl-2-(4-fluorophenyl)-6-rr(2-hvdroxy-2,5-dihvdro-1 ,2-oxaborol-4- yl)methyll(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

Step 1 : ( 2Z)-3-bromo-2-({[( methyloxy)methyl]oxy}methyl)-2-propen- 1 -ol

A solution of ethyl (2E)-3-bromo-2-({[(methyloxy)methyl]oxy}methyl)-2-propenoate {Journal of Organic Chemistry, 2007, 72, p. 6143); (1.37 g, 5.41 mmol) in tetrahydrofuran (80 mL) at 0 °C was treated with DIBALH (32.5 mL, 32.5 mmol) and maintained with stirring for 3 hours. The solution was quenched by addition of 10% aqueous Rochelle's Salt and then further diluted with ethyl acetate. The mixture was maintained with rapid stirring for 5 hours, and then the organic layer was separated, dried over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford (2Z)-3-bromo-2-({[(methyloxy)methyl]oxy}methyl)-2- propen-1-ol (980 mg, 4.64 mmol, 86 % yield) as clear oil. ¹H NMR (CHLOROFORM-d) δ: 6.41 (s, 1 H), 4.69 (s, 2H), 4.37 (s, 2H), 4.23 (s, 2H), 3.42 (s, 3H).

Step 2: 6-[[(2Z)-3-bromo-2-({[(methyloxy)methyl]oxy}methyl)-2-propen-1- yl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-m

carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-

1- benzofuran-3-carboxamide (800 mg, 1 .988 mmol), (2Z)-3-bromo-2-

({[(methyloxy)methyl]oxy}methyl)-2-propen-1-ol (839 mg, 3.98 mmol), and triphenylphosphine (1 173 mg, 4.47 mmol) in tetrahydrofuran (25 mL) was maintained with stirring at 0 °C and treated drop wise with DIAD (0.773 mL, 3.98 mmol). The mixture was warmed to room temperature, stirred for 5 hours, and mixed with celite. All volatiles were removed under reduced pressure and the residue was purified by column chromatography to afford 6-[[(2Z)- 3-bromo-2-({[(methyloxy)methyl]oxy}methyl)-2-propen-1-yl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (800 mg, 1.343 mmol, 67.6 % yield) as a white foam. LCMS {m/z, ES⁺) = 597 (M+H)

Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-2,5-dihydro-1,2-oxaborol-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[[(2Z)-3-bromo-2-({[(methyloxy)methyl]oxy}methyl)-2-propen-1- yl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1 -benzofuran-3- carboxamide (750mg, 1 .259 mmol), potassium acetate (494 mg, 5.04 mmol),

bis(pinacolato)diboron (800 mg, 3.15 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (103 mg, 0.126 mmol) in 1 ,4-dioxane (15 mL) was maintained with stirring at 50 °C for 16 hours. The mixture was cooled to room temperature, 5. ON HCI (aq) (12 mL) was added, and stirring was continued for 3 hours. The solution was filtered through glass filter paper, diluted with ethyl acetate, and the organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc to afford 5-cyclopropyl-

2- (4-fluorophenyl)-6-[[(2-hydroxy-2,5-dihydro-1 ,2-oxaborol-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide (92 mg, 0.185 mmol, 14.66 % yield) as a white solid following lyophilization. ¹H NMR (METHANOL-d₄) δ: 7.91 (dd, J = 8.5, 5.4 Hz, 2H), 7.68 (s, 1 H), 7.24 (t, J = 8.7 Hz, 2H), 7.1 1 (s, 1 H), 5.62 (s, 1 H), 4.51 - 4.69 (m, 4H), 3.12 (s, 3H), 2.93 (s, 3H), 2.36 (t, J = 8.2 Hz, 1 H), 1.07 (br. s., 2H), 0.91 (br. s., 1 H), 0.64 (br. s., 1 H). LCMS {m/z, ES⁺) = 499 (M+H)

Example 30

5-cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)propan-2- ylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: Ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(isopropylsulfonyl)propan-2- ylsulfonamido)benzofuran-3-carboxylate

To a solution of ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxylate (1 .2g, 3.5 mmol) in dry dichloromethane (15 mL) at -15 °C under N₂ atmosphere was added triethylamine (1 .30 mL, 8.8 mmol), then drop wise propane-2-sulfonyl chloride

(1 .75 g, 12.2 mmol). The solution was warmed to room temperature and stirred for 1 hour.

The reaction mixture was diluted with water (10 mL) and extracted with DCM (3x20mL),The organic layers were combined, dried with MgS0₄, filtered, and evaporated under vacuum to afford ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(isopropylsulfonyl)propan-2- ylsulfonamido)benzofuran-3-carboxylate (1.3g, 67 %).

Step 2: 5-cyclopropyl-2-(4-fluorophenyl)-6-( 1-methylethylsulfonamido)benzofuran-3- carboxylic acid

Potassium hydroxide (1 .51 g, 27 mmol) was added to a solution of ethyl 5- cyclopropyl-2-(4-fluorophenyl)-6-(N-(isopropylsulfonyl)propan-2-ylsulfonamido)benzofuran-3- carboxylate (1 .00g, 1 .8 mmol) in ethanol (14 mL) and water (7 mL) under nitrogen. The reaction was heated to reflux and stirred for 1 hour, then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 N HCI (20 mL) until a precipitate formed. The solid was filtered and dissolved in EtOAc (200 ml), dried and concentrated to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-(1 - methylethylsulfonamido)benzofuran-3-carboxylic acid (white solid, 0.6g, 80%). Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(1-methylethylsulfonamido)benzofuran- 3-carboxamide 5-cyclopropyl-2-(4-fluorophenyl)-6-(1-methylethylsulfonamido)benzofuran-3-carboxyli acid (0.6g, 1.44 mmol) was dissolved in dry N,N-dimethylformamide (15 mL) at 21 °C with DIPEA (0.55 ml, 3.17 mmol) and HATU (0.65 g, 1 .73 mmol), stirred for 15 minutes, and then 2M methylamine (2.88 mL, 5.76 mmol) in THF was added. The solution was stirred for 2 hours and evaporated to dryness. The residue was dissolved in ethyl acetate, and washed with saturated sodium bicarbonate solution and then 2M HCI (20 ml). The organic layers were separated and dried using anhydrous MgS0₄, filtered, and concentrated under reduced pressure. The residue was purified using column chromatograph (EA PE=1 :2) to obtain 5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(1 -methylethylsulfonamido)benzofuran-3- carboxamide as a pale white solid(260 mg, 42%).

Step 4: 6-(N-(2-(benzyloxymethyl)allyl)propan-2-ylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(1- methylethylsulfonamido)benzofuran-3-carboxamide (0.26g, 0.6 mmol), Kl (5 mg, 0.03 mmol) and K₂C0₃ (0.248 g, 1 .8 mmol) in dry DMF (10 mL) was treated with ((2- (bromomethyl)allyloxy)methyl)benzene (298 mg, 1 .2 mmol) and the reaction mixture stirred at room temperature under nitrogen for half an hour. The reaction was diluted with water (30 mL) and extracted with EtOAc (3^*60 mL). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The crude product was purified by column

chromatography (EA:PE = 1 :2) to give the 6-(N-(2-(benzyloxymethyl)allyl)propan-2- ylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (320 mg, 90%) . Step 5: 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methyl)propyl)propan-2-ylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (34mg, 0.05 mmol) and 6-(N-(2- (benzyloxymethyl)allyl)propan-2-ylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (320 mg, 0.5mmol) were dissolved in THF (10 mL) under a nitrogen atromsphere. Pinacolborane (640 mg, 5 mmol) was added and the mixture stirred for 3 hours. The solvent was removed in vacuo and the crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to give 6-(N-(3-(benzyloxy)-2- ((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl)propyl)propan-2-ylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (330 mg, 85% yield). Step 6: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-( ( 2-hydroxy-1 ,2-oxaborolan-4-yl)methyl) propan-2-ylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)propan-2-ylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (330 mg, 0.46 mmol) was dissolved in THF (15 mL), 130 mg of Pd/C (10%) was added and stirred under H₂ (50 PSI) at room temperature for 16 hours. The mixture was filtered and concentrated. The residue was dissolved in THF (15 mL) and treated with 5 N HCI (0.46 mL) and PS-benzene boronic acid (898mg, 2.3mmol). The suspension was stirred for 2 hours, filtered, and concentrated under reduced pressure. The residue was redissolved in THF (15 mL) and treated with 5 N HCI (0.46 mL) and PS-benzene boronic acid (898mg, 2.3 mmol). The suspension was stirred for 2 hours, filtered, and concentrated under reduced pressure. The crude product was purified by preparatory-HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4-yl)methyl)propan- 2-ylsulfonamido)-N-methylbenzofuran-3-carboxamide (90mg, 37% yield). LCMS (m/z) ES⁺ =528.9 (M+1 ). ¹H NMR (300 MHz, CD₃OD) δ = 7.84-7.79 (m, 2H), 7.58-7.54 (d,j =12 Hz, 1 H), 7.18-7.12 (m, 2H), 6.99 (s, 1 H), 3.91-3.50 ( M, 4H), 3.48-3.39 (m, 1 H), 2.84 (S, 3H), 2.37-2.29 (m, 1 H), 2.21 -2.06 (m, 1 H), 1 .37-1.25 (m, 6H), 1 .02-0.82 (m, 4H), 0.74-0.56 (m, 2H). Example 31

N,5-dicvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide

Step 1: N, 5-dicyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3- carboxamide

5-Cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (1 .0 g, 2.568 mmol) was stirred in dry DMF (15 mL) at ambient temperature with DIPEA (730 mg, 5.650 mmol) and HATU (1 .71 g, 3.082 mmol). After stirring for 15 minutes,

cyclopropanamine (587 mg, 10.272 mmol) in 15 mL of THF was added. The reaction mixture was stirred for 2 hours and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 ml_), dried over anhydrous Na₂S0₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0- 50% ethyl acetate in petroleum) to give N,5-dicyclopropyl-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxamide (1 .4 g, crude, 1 19% yield).

Step 2: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-N, 5-dicyclopropyl-2-(4- fluorophenyl)benzofuran-3-carboxamide.

A suspension of N,5-dicyclopropyl-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxamide (1 .4 g, crude, 2.825mmol), Kl (47 mg, 0.2825 mmol) and K₂C0₃ (1.17 g, 8.475 mmol) in dry DMF (10 mL) was treated with ((2-

(bromomethyl)allyloxy)methyl)benzene (1.49 g, 6.215mmol) and the reaction mixture was heated to reflux under nitrogen for 30 minutes. The reaction was cooled, diluted with water (15 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(2-

(benzyloxymethyl)allyl)methylsulfonamido)-N,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (726 mg, 44% yield) . LCMS (m/z, ES⁺) = 589 (M+1 )⁺

Step 3: 6-(N-(3-(benzyloxy)-2-((4,4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-N,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (85 mg, 0.123 mmol) and 6-(N-(2- (benzyloxymethyl)allyl)methylsulfonamido)-N,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (726 mg, 1.23mmol) were dissolved in THF (10 mL) under a nitrogen atmosphere. Pinacolborane (788 mg, 6.15 mmol) was added and the mixture stirred for 3 h at room temperature. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(3- (benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-N,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (863 mg, 98% yield).

Step 4: N, 5-dicyclopropyl-2-(4-fluorophenyl)-6-(N-( ( 2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-N,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (863 mg, 1 .205 mmol) was dissolved in THF (10 mL). 942 mg of Pd/C (10%) was added and stirred under H₂ (60 PSI) at room temperature for 6 h. The mixture was filtered and concentrated. The residue was dissolved in THF (10 mL) and treated with 5 N HCI (1 .4 mL) and PS-benzene boronic acid (2.57 g, 6.69 mmol). The suspension was stirred for 4 hours, filtered, and concentrated in vacuo. The residue was purified by pre-HPLC to give N,5-dicyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide (1 13 mg, 21 % yield). 1 H NMR (300 MHz, CD30D-d4) δ = 7.95(m, 2H), 7.74(d,1 H),7.31 (t, 2H),7.12 (s, 1 H), 3.81 ( m, 2H), 3.68(m, 1 H), 2.99 (s, 3H),2.95(m, 1 H),2.50 (m, 1 H), 2.38 (m, 1 H), 1.1 1 (m, 3H),0.91 (m, 4H),0.74 (m, 4H).LCMS( m/z) ES⁺=527(M+1 ) Example 32

5-Cvclopropyl-2-(4-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide

Step 1 : 5-Cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxamide 5-Cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid

(600 mg, 1 .542 mmol) was stirred in dry DMF (15 mL) at ambient temperature and DIPEA (439mg, 3.392 mmol) and HATU (704mg, 1.85 mmol) were added. After stirring for 15 minutes, ammonia (104 mg, 6.169 mmol) in 15 mL of THF was added. The reaction mixture was stirred for another 2 hours and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL x2).

The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated in vacuo. The residue 5-cyclopropyl-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxamide (1 .0 g, crude) was used for the next step without further purification.

Step 2: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)benzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3- carboxamide (1 .0 g, crude, 1.542mmol), Kl (256 mg, 1.542 mmol) and K₂C0₃ (639 mg, 4.626 mmol) in dry DMF (10 mL) was treated with ((2-(bromomethyl)allyloxy)methyl)benzene (815 mg, 3.392 mmol) and the reaction mixture was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (15 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)benzofuran-3-carboxamide (574 mg, 67% yield) . LCMS (m/z, ES⁺) = 571 (M+1 )⁺

Step 3: 6-(N-(3-(benzyloxy)-2-((4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofu

carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (72 mg, 0.1 mmol) and 6-(N-(2-

(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (570 mg, 1.04mmol) were dissolved in THF (10 ml.) under a nitrogen atromsphere. Pinacolborane (666 mg, 5.2 mmol) was added and the mixture stirred for 3 hours at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(3- (benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (906 mg, 128% yield). Step 4: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide

A solution of 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (906 mg, crude, 1 .04 mmol) in THF (10 ml.) was treated with 906 mg of Pd/C (10%) and stirred under H₂ (60 PSI) at room temperature for 6 hours. The mixture was filtered and concentrated. The residue was dissoved in THF (10 ml.) and treated with 5 N HCI (1 .4 ml.) and PS-benzene boronic acid (2.0 g, 7.28 mmol). The suspension was stirred for 4 hours, filtered, concentrated in vacuo. The residue was purified by pre-HPLC to give 5- cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)benzofuran-3-carboxamide (201 mg, 40% yield). 1 H NMR (300 MHz, CD30D-d4) δ = 8.05(m, 2H), 7.75(d,1 H),7.31 (q, 3H),7.12 (s, 1 H), 3.82( m, 4H), 3.10 (s, 3H), 2.50 (m, 2H),1 .12 (m, 3H),0.96 (m, 2H),0.73 (m, 1 H).LCMS( m/z) ES⁺=487(M+1 )

Example 33

5-cvclopropyl-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N-methyl-2- (4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide

Step 1: ethyl 3-(4-(trifluoromethyl)phenyl)-3-oxopropanoate

To a solution of 4-(trifluoromethyl)benzoic acid (30.0 g, 0.58 mol) in DCM (250 mL) was added oxalyl chloride (21 mL, 0.237 mol), then DMF (0.5 mL) was added drop wise. The reaction mixture was refluxed for 2 hrs. The resulting clear yellow solution was concentrated in vacuo. The acid chloride was obtained as yellow liquid. To a solution of ethyl potassium malonate (34g, 0.2 mol) in MeCN (500 mL) was added TEA (55 mL) and cooled in an ice-salt bath, MgCI₂ (23 g, 0.242 mol) was added, and the resulting mixture was stirred at that temperature for 3 hrs. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. After the reaction was complete (monitored by TLC), the mixture was cooled in an ice bath and the intermediate was treated with 2N HCI (600 mL) via careful addition. This mixture was stirred in an ice bath for 1.5 hours and then transferred to a separatory funnel and extracted with EA (3x200 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate (450 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product ethyl 3-(4-(trifluoromethyl)phenyl)-3-oxopropanoate (42 g, 102 %). It was used without purification for further step.

Step 2: ethyl 2-(4-(trifluoromethyl)phenyl)-5-hydroxybenzofuran-3-carboxylate

Zinc chloride (22.9 g, 0.169 mol) was stirred in anhydrous ethanol (45 mL) then heated to 95 °C (reflux) under nitrogen atmosphere using oven dried glassware. Ethyl 4- (trifluoromethyl)benzoylacetate (41.2 g, 0.158 mol) was added as a single portion followed by dropwise addition of a solution of benzoquinone (18.4 g, 0.171 mol) in anhydrous MTBE (500 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155 °C and an internal temperature of 75-95 °C maintained throughout most of the addition. Half way through the addition more anhydrous ethanol (45 mL) was added because the reaction mixture became thick and a loss of some of the organic volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried and evaporated under vacuum. The residual brown solid was slurried in warm dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give ethyl 2-(4- (trifluoromethyl)phenyl)-5-hydroxybenzofuran-3-carboxylate (16.6 g, 30 %).

Step 3: ethyl 2-(4-(trifluoromethyl)phenyl)-5-isopropoxybenzofuran-3-carboxylate

Ethyl 2-(4-(trifluoromethyl)phenyl)-5-hydroxybenzofuran-3-carboxylate (14.94 g, 0.047 mol) was dissolved in NMP (155 mL). Isopropyl bromide (13.8 mL) was added, followed by cesium carbonate (30.7 g, 0.094 mol). The reaction mixture was stirred in a 60 °C oil bath for 20 hrs then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 min. This mixture was then diluted with water and extracted with hexane. The combined organic layers were washed with water, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give ethyl 2-(4- (trifluoromethyl)phenyl)-5-isopropoxybenzofuran-3-carboxylate (17.6 g, 94%).

Step 4: Ethyl 5-isopropoxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate

Ethyl 5-isopropoxy-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate 4 (17.6 g, 0.045 mol) was dissolved in chloroform (41 mL) and the resulting solution was cooled in an ice bath. Nitric acid (29.5 mL) was also dissolved in chloroform (41 mL) and cooled in an ice bath. The acid solution was added to the solution of ethyl 2-(4-(trifluoromethyl)phenyl)-5- isopropoxybenzofuran-3-carboxylate over 1 hour, and the reaction mixture was then stirred at 0°C for 1.5 hours. The reaction mixture was then diluted with water (80 mL), the organic layer was separated, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. It was purified by column chromatography (PE/EA=5/1 ) to afford ethyl 5- isopropoxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate as a brown solid (5.2 g, 26.5 %).

Step 5: Ethyl 5-hydroxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate

Ethyl 5-isopropoxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate (6 g, 2.28 mmol) was dissolved in anhydrous DCM (50 mL) and cooled in an ice bath under an atmosphere of nitrogen. Boron trichloride (4.2 mL, 6.86 mmol) was added over 30 min. After the reaction was complete, the reaction mixture was quenched by pouring onto an ice/water mixture. The reaction mixture was washed into the ice/water mixed with DCM. The mixture was extracted with DCM (3x50 ml), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give ethyl 5-hydroxy-6- nitro-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate ( 3.8 g, 28 %). Step 6: Ethyl6-nitro-2-(4-(trifluoromethyl)phenyl)-5-(trifluoromethylsulfonyloxy)be carboxylate

A mixture of ethyl 5-hydroxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran- 3- carboxylate (3.8 g, 9.6 mmol) in anhydrous DCM (60 mL) was added DMAP (0.1 17 g, 0.96 mmol) and anhydrous TEA (1 .9 g, 19.2mol). The resulting mixture was cooled in an ice bath under nitrogen, then trifluoromethane sulfonic anhydride (4.06, 14.4 mmol) was added. The reaction mixture was stirred under nitrogen at 0 °C for 30 minutes, quenched at 0 °C with water (100 mL), and extracted with DCM (3x100 mL). The combined organic layers were washed with water (3x200 mL), 2N HCI (2x100 mL), water (200mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give methyl 6-nitro-2-(4-

(trifluoromethyl)phenyl)-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (5.7 g, 105 %) as a yellow solid. This material was used without further purification.

Step 7:

ethyl 5-cyclopropyl-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate

Ethyl 6-nitro-2-(4-(trifluoromethyl)phenyl)-5-(trifluoromethylsulfonyloxy)benzofuran-3- carboxylate (5.7 g, 10.8 mmol), KF (2.0 g, 35.6 mmol), NaBr (1 .1 g, 10.6mmol),

cyclopropylboronic acid (1 .4 g, 16.2 mmol) and Pd(Ph₃P)₄ (0.62 g, 0.09 mmol) were dissolved in a mixture of toluene (80 mL) and water (1 .45 mL). The reaction flask was evacuated for ~3 min then filled under nitrogen. The reaction mixture was refluxed under nitrogen for 20 hrs then cooled to ambient temperature. The reaction mixture was quenched with water (500 ml) and extracted with EtOAc (3x1 L), washed with water (3x1 L), brine (3x1 L), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (PE/EA = 2:1 ) to afford ethyl 5-cyclopropyl-6-nitro-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxylate (3.5 g, 78 %) as a yellow solid.

Step 8: Ethyl 6-amino-5-cyclopropyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate A solution of ethyl 5-cyclopropyl-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran- 3- carboxylate (3.5 g, 8.3 mmol) in ethyl acetate (200 mL) was added 10% Palladium on activated carbon (1.0 g), 1 N HCI (0.95 mL), and stirred under 0.4 MPa of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give ethyl 6-amino-5-cyclopropyl-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxylate as a brown solid (crude, 3.5 g, 95 %). Step 9: Ethyl 5-cyclopropyl-6-(N-(methylsulfonyl)methylsulfonamido)-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxylate A solution of methyl 6-amino-5-cyclopropyl-2-(4-(trifluoromethyl)phenyl) benzofuran-3- carboxylate (3.2 g, 8.2 mmol) in dry dichloromethane (50 mL) at -15 °C under N₂

atmosphere was added dry TEA (2.07 g, 20.5 mmol) then added drop wise methanesulfonyl chloride (3.27 g, 28.7 mmol). The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (50ml_) and extracted with DCM (3x50 mL). The organic layers were combined, dried over Na₂S0₄, filtered,

concentrated and added EtOAc (10 ml). The residue was cooled to 0 °C for 1 h. The solid was filtered, washed with EtOAc (0 °C, 5 ml) and dried in air to afford ethyl 5-cyclopropyl-6- (N-(methylsulfonyl)methylsulfonamido)-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylate (4.7 g, 105 %).

Step 10: 5-cyclopropyl-6-(methylsulfonamido)-2-(4-(trifluoromethyl)phenyl)benzofuran carboxylic acid

Potassium hydroxide (5.6 g, 100.6 mmol) was added to a solution of ethyl 5- cyclopropyl-6-(N-(methylsulfonyl)methylsulfonamido)-2-(4-

(trifluoromethyl)phenyl)benzofuran-3-carboxylate in ethanol (60 mL) and water (30 mL) under nitrogen. The reaction was refluxed for 1 hour, and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 N HCI until a precipitate formed. The solid was filtered and then dried in air to afforded 5-cyclopropyl-6- (methylsulfonamido)-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylic acid (3.1 g, 82 %). This material was used without further purification.

Step 11: 5-cyclopropyl-N-methyl-6-(methylsulfonamido)-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxamide

5-cyclopropyl-6-(methylsulfonamido)-2-(4-(trifluoromethyl)phenyl)benzofuran-3- carboxylic acid (3.1 g, 7.06 mmol) in dry DMF (30 mL) was added DIPEA (2.2 g, 14.0 mmol) and HATU (3.1 g, 8.4 mmol) at 21 °C, after stirring for 15 minutes 2M methylamine in THF (13.6 mL, 27.2 mmol) was added. The mixture was stirred for another 2 hours then added water (60 mL). The mixture was extracted with EA (3^*100 mL), washed with saturated NaHCO₃ (100 ml), 2M HCI (100 ml), water (100 mL) and brine (100 ml), dried over Na₂S0₄, concentrated and purified by column chromatography to afford 5-cyclopropyl-N-methyl-6- (methylsulfonamido)-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide as a white solid (2.7 g, 88%). Step 12: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxamide A solution of 5-cyclopropyl-N-methyl-6-(methylsulfonamido)-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxamide (2.2 g, 4.86 mmol) in dry DMF (20 mL) was added potassium carbonate (2.0 g, 14.5 mmol), Kl (81 mg, 0.49 mmol) and ((2- (bromomethyl)allyloxy)methyl)benzene (1.76 g, 7.29 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 2 hour, then diluted with water (60 mL), extracted with EtOAc (3x100 ml), washed with water (100 mL) and brine (100 mL), dried and concentrated in vacuo to afford the crude product. The residue was purified by column chromatography (EA PE = 1 :2) to give 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5- cyclopropyl-N-methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide as a brown solid (1 .5 g, 52 %).

Step 13 : 6-(N-(3-(benzyloxy)-2-((4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(4-

(trifluoromethyl)phenyl)benzofuran-3-carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (192 mg, 0.26 mmol) and 6-(N-(2-

(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxamide (1.5 g, 2.6 mmol) were dissolved in THF (50 mL) under nitrogen atmosphere. Pinacolborane (3.3 g, 26 mmol) was added and the mixture was stirred for 24 h. The solvent was removed in vacuo and the crude product was purified by column chromatography (solvent: 0-50 %, ethyl acetate in petroleum) to give 6-(N- (3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxamide as a yellow solid (1.4 g, 79 %). Step 14: 5-cyclopropyl-6-(N-((2-hydroxy-1,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N- methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(4-

(trifluoromethyl)phenyl)benzofuran-3-carboxamide (1.4 g, 2.0 mmol) was dissloved in THF (30 mL) and 1.38 g of Pd/C (10%) was added. The mixture was stirred under hydrogen (40 PSI) at room tempurature for 16 hours. The mixture was filtered and concentrated. The residue was dissolved in THF (30 mL) and treated with 5 N HCI (2.8 mL) and PS-benzene boronic acid (3.65 g, 10 mmol). The suspention was stirred for 2 hours, then filtered and concentrated in vacuo. The residue was redissolved in THF (30 mL) and treated with 5 N HCI (2.8 mL) and PS-benzene boronic acid (3.65 g, 10 mmol). The suspension was stirred for 2 hours, then filtered and concentrated in vacuo. The crude product was purified by pre-HPLC to give 5-cyclopropyl-6-(N-((2-hydroxy-1 ,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N- methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide as a white solid (320 mg, 30 %).

LCMS (m/z) ES⁺= 550.8 (M+1 ). ¹ H NMR (300 MHz, CD₃OD) δ = 7.94-7.91 (m, 2H), 7.69- 7.60 (m, 3H), 7.02 (s, 1 H), 3.95-3.40 (m, 4H), 2.97 (s, 3H), 2.85 (S, 3H), 2.39-2.28 (m, 1 H), 2.24-2.02 (m, 1 H), 1.05-0.50 (m, 6H)

Example 34

2-(4-chlorophenyl)-5-cvclopropyl-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: ethyl 3-(4-chlorophenyl)-3-oxopropanoate

A solution of 4-chlorobenzoic acid (30.0 g, 0.192 mol) in DCM (250 mL) was added oxalyl chloride (25 mL, 0.288 mol), then DMF (0.5 mL) was added dropwise. The reaction mixture was refluxed for 2 hours. The resulting clear yellow solution was concentrated in vacuo. The acid chloride was obtained as yellow liquid. A solution of ethyl potassium malonate (41 g, 0.241 mol) in MeCN (537 mL) was added TEA (67 mL) and cooled in an ice- salt bath, MgCI₂ (27.4 g, 0.288 mol) was added, and the resulting mixture was stirred at that temperature for 3 hours. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. After the reaction was complete, the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2N HCI (600 mL). This mixture was stirred in the ice bath for 1.5 hrs then transferred to a separatory funnel and extracted with EA (3x200 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate (450 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product ethyl 3-(4-chlorophenyl)-3-oxopropanoate ( 48.6 g, 1 10 % yield). It was used without purification for further step.

Step 2: ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate

Zinc chloride (28.3 g, 0.207 mol) was stirred in anhydrous ethanol (45 mL) then heated to 95 °C (reflux) under nitrogen atmosphere using oven dried glassware. Ethyl 4- Chlorobenzoylacetate (44 g, 0.194 mol) was added in a single portion followed by dropwise addition of a solution of benzoquinone (22.6 g, 0.21 mol) in anhydrous MTBE (500 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155 °C and an internal temperature of 75-95 °C maintained throughout most of the addition. Half way through the addition more anhydrous ethanol (45 ml.) was added because the reaction mixture became thick and a loss of some of the orginal volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 ml.) and EtOAc (250 ml_). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried and evaporated under vacuum. The residual brown solid was slurried in warm

dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give the benzofuran (27 g, 43.9 %). Step 3: ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate

Ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (26 g, 0.051 mol) in NMP (160 mL) was added Isopropyl bromide (15 ml_), then cesium carbonate (33 g, 0.101 mol) was added. The reaction mixture was stirred in a 60 °C oil bath for 20 hrs then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 min. This mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3- carboxylate (15 g, 82 %). Step 4: ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (30 g, 0.084 mol) was dissolved in chloroform (75 mL) and the resulting solution was cooled in an ice bath. Nitric acid (55 mL) was also dissolved in chloroform (75 mL) and cooled in an ice bath. The acid solution was added dropwise to the solution of compound ethyl 2-(4-chlorophenyl)-5- isopropoxybenzofuran-3-carboxylate over 1 hour, and the reaction mixture was then stirred at 0°C for 1 .5 hrs. The reaction mixture was then diluted with water (60 mL), and the layers were separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil .It was purified by column chromatography ( PE/EA = 5/1 ) to afford ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as a brown solid (1 1 g, 32.4 %).

Step 5: Ethyl 2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate Ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (1 1 g, 27.2 mmol) was dissolved in anhydrous DCM (150 ml.) and cooled in an ice bath under an atmosphere of nitrogen. Boron trichloride (41 ml_, 41 .0 mmol) was added over 20 minutes. After the reaction was complete, the mixture was quenched by pouring into an ice/water mixture. The reaction mixture was poured into the ice/water mixed with DCM. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give compound ethyl 2-(4- chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate ( 10.2 g, 84 %). Step 6: Ethyl-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsu

A solution of ethyl 2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (10.2 g, 22.9 mmol) and DMAP (0.289 g, 2.3 mmol) in anhydrous DCM (300 ml.) and anhydrous TEA (4.8 ml.) in an ice bath under nitrogen was added trifluoromethane sulfonic anhydride (5.62ml_, 34 mmol). The reaction mixture was stirred under nitrogen at 0°C for 30 min then quenched at 0 °C with water (200 ml.) and extracted with DCM (3x200 ml_). The combined organic layers were washed with water (3x^*600 ml_), 2N HCI (2^*300 ml_), water (300ml_), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. Ethyl 2-(4- chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (10 g, 80 %) was obtained as a yellow solid. It was used without further purification.

Step 7: Ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate

A mixture of 2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3- carboxylate (10 g, 18 mmol), KF (4.64 g, 79.9 mmol), NaBr (2.48 g, 24 mmol),

cyclopropylboronic acid (3.2 g, 37 mmol), and Pd(Ph₃P)₄ (1.33 g, 1.15 mmol) were dissolved in toluene (130 ml.) and water (2.8 ml_). The reaction flask was evacuated for ~3 minutes then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hrs then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (150 ml_), washed with water (3x200 ml_), brine (200 ml_), dried with anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ ethyl acetate = 30/1 -10/1 ) to give a yellow solid (7.9 g, 99 %).

Step 8: Ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate

To a solution of ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3- carboxylate (8 g, 18.2 mmol) in ethyl acetate (450 ml.) was added 10% palladium on activated carbon (1 .83 g), 1 N HCI solution (2.5 ml_), and stirred with under 0.4 MPa of hydrogen at room temperature for 8 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give the amine as a brown solid (7.4 g, 99 %).

Step 9:

ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-

(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate

To a solution of ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3- carboxylate (7.4 g, 18.06 mmol) in dry dichloromethane (170 mL) at -15 °C under N₂ atmosphere was added dry TEA (6.73 mL, 45.15 mmol), and then methanesulfonyl chloride (4.91 mL, 63.2 mmol) was added drop wise. The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3x150mL). The organic layers were combined, dried with NaS0₄, filtered, and evaporated under vacuum to afford ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N- (methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate (9.2 g, 99 %). This material was used without further purification.

Step 10: 5-Cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid

Potassium hydroxide(15.1 g, 270 mmol) was added to a solution of the ethyl 2-(4- chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3- carboxylate in ethanol (64 mL) and water (32 mL) under nitrogen atmosphere. The reaction was refluxed for 1 hour, and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 N HCI (250 mL) until a precipitate formed. The solid was filtered and then dried to afforded 5-cyclopropyl-2-(4-chlorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxylic acid (8.7 g, 1 1 1 %). This material was used without further purification.

Step 11: 5-Cyclopropyl-2-(4-chlorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide

A solution of 5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3- carboxylic acid (5 g, 1 1 .52 mmol) in dry DMF (30 mL) was added with DIPEA (3.3 g, 25.34 mmol), HATU (5.15 g, 13.5 mmol) at 20 °C. After 15 minutes, 2M methylamine in THF(23.04 mL, 46.08 mmol) was added drop wise and the mixture was stirred for another 2 hours then added water (60ml). The mixture was extracted with EA (3x200 mL), washed with water (2^*200 mL), dried and concentrated to afford 5-cyclopropyl-2-(4-chlorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran -3-carboxamide as a brown solid (4.7 g, 97 %). Step 12: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-2-(4-chlorop

cyclopropyl-N-methylbenzofuran-3-carboxamide

Potassium carbonate(1 g, 7.17 mmol), Kl (0.397 g, 2.39 mmol) and (2- bromomethylallyloxymethyl)benzene (1 .15 g, 4.78 mmol) were added to a solution of 5- cyclopropyl-2-(4-chlorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (1 g, 2.39 mmol) in dry DMF (10 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, then diluted with water (30 mL), and filtered. The residue was dissolved in EA, dried and concentrated in vacuo and purified by column chromatography (first EA/PE=1 :10, then EA/PE=1 :2) to give 6-(N-(2- (benzyloxymethyl)allyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N- methylbenzofuran-3-carboxamide as a brown solid(0.97 g, 70 %).

Step 13: 6-(N-(3-(benzyloxy)-2-((4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofum 3-carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (1 15.4 mg, 0.167 mmol) and 6- (N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N- methylbenzofuran-3-carboxamide (970 mg, 1.67 mmol) were dissolved in THF (12 mL) under nitrogen atromsphere. Pinacolborane (1.07 g, 8.35 mmol) was added and the mixture was stirred for 24 hours. The solvent was removed in vacuo and the crude residue was purified by column chromatography (first EA PE=1 :5, then EA PE=1 :2) to give 6-(N-(3- (benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran- 3-carboxamide (1 g, 55 %).

Step 14: 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-((2-hydroxy-1,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran- 3-carboxamide(1 g, 1.41 mmol) was dissloved in THF (15 mL). 300 mg of activated palladium on carbon (10%) was added and stirred under hydrogen (40 PSI) at room tempurature for 48 hours. The mixture was filtered and concentrated. The residue was dissoved in THF (15 mL) and treated with 5 N HCI (1 .97 mL) and PS-benzene boronic acid (2.74 g, 7.05 mmol). The suspension was stirred for 3 hours, then filtered and concentrated in vacuo.T e crude product was purified by preparatory HPLC to give 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-((2- hydroxy-1 ,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide as a white solid (130 mg, 18 % yield). ¹H NMR (300MHz, CD30D) δ =7.90-7.87(d,2H), 7.75- 7.71 (d, 1 H), 7.55-7.52(m,2H), 7.14(s, 1 H),3.85-3.63(m,4H),3.09(s,3H), 2.97(s,3H),

2.46(m,1 H), 2.24(m, 1 H), 1.10(m,2H), 0.95-0.88(m,2H), 0.70(m,2H) LCMS( m/z)

ES+=516.8(M+1 ) Example 35

5-cvclopropyl-2-(3-fluorophenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: ethyl 3-(3-fluorophenyl)-3-oxopropanoate

To a mixture of 4-fluorobenzoic acid (30.0 g, 0.214 mol) in DCM (150 mL) was added oxalyl chloride (28 mL, 0.33 mol), then DMF (0.5 mL) was added dropwise. The reaction mixture was then heated to reflux with stirring for 2 hrs. The resulting clear yellow solution was concentrated in vacuo. The acid chloride was obtained as yellow liquid. A mixture of ethyl potassium malonate (45.6 g, 0.268 mol) and TEA (75 mL) in MeCN (600 mL) was cooled in an ice-salt bath, MgCI₂ (30.6 g, 0.322 mol) was added and the resulting mixture was stirred at this temperature for 3 hours. The acid chloride prepared above was added, and the reaction mixture was warmed to room temperature and stirred overnight. After the reaction was complete the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2N HCI (500 mL). This mixture was stirred in the ice bath for 1 .5 hours and then transferred to a separatory funnel and extracted with EA (3x200 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate (500 mL), brine (250 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude of ethyl 3-(3-fluorophenyl)-3-oxopropanoate ( 48.4 g, quant.). It was used without purification for next step.

Step 2: ethyl 2-(3-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate

Zinc chloride (31 g, 0.229 mol) was stirred in anhydrous ethanol (45 mL) then heated to 95 °C (reflux) under an atmosphere of nitrogen using oven dried glassware. Ethyl 3- fluorobenzoylacetate (45 g, 0.214 mol) was added as a single portion followed by dropwise addition of a solution of benzoquinone (25 g, 0.231 mol) in anhydrous MTBE (500 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155 °C and an internal temperature of 75-95 °C maintained throughout most of the addition. Half way through the addition more anhydrous ethanol (45 mL) was added because the reaction mixture became thick and a loss of some of the orginal volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried and evaporated under vacuum. The residual brown solid was slurried in warm

dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give the benzofuran (14.6 g, 22.8 %).

Step 3: ethyl 2-(3-fluorophenyl)-5-isopropoxybenzofuran-3-carboxylate

To a solution of ethyl 2-(3-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (14.6 g,

0.049 mol) in NMP (160 mL) was added isopropyl bromide (14.2 mL), then cesium carbonate (32 g, 0.098 mol) was added. The reaction mixture was stirred in a 60 °C oil bath for 20 hours and then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 minutes. This mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give ethyl 2-(3-fluorophenyl)-5- isopropoxybenzofuran-3-carboxylate (14.8 g, 89 %).

Step 4: ethyl 2-(3-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(3-fluorophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (14.8 g, 43.3 mol) was dissolved in chloroform (40 mL) and the resulting solution was cooled in an ice bath. Nitric acid (28.5 mL) was also dissolved in chloroform (40 mL) and cooled in an ice bath. The acid solution was added to the solution of ethyl 2-(3-fluorophenyl)-5-isopropoxybenzofuran-3- carboxylate over 1 hour, and the reaction mixture was then stirred at 0°C for 1 .5 hours. The reaction mixture was then diluted with water (60 mL) , and the organnic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. It was purified by column chromatography PE/EA=5/1 ) to give the pure ethyl 2-(3- fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as a pale orange solid (4.2 g, 25 %).

Step 5: Ethyl 2-(3-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate Ethyl 2-(3-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (4.2 g, 10.9 mmol) was dissolved in anhydrous DCM (56 mL) and cooled in an ice bath under an atmosphere of nitrogen. Boron trichloride (16.3 mL, 16.3 mmol) was added over -20 minutes. After the reaction was complete, the reaction mixture was quenched by pouring into an ice/water mixture. The reaction mixture was poured into the ice/water mixed with DCM. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give ethyl 2-(3- fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate ( 4.3 g, 1 15 %). It was without purification for next step.

Step 6: Ethyl 2-(3-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3- carboxylate

To a mixture of ethyl 2-(3-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (4.2 g, 1 1 mmol) and DMAP (0.139 g, 1 .1 mmol) were added anhydrous DCM (160 mL) and anhydrous TEA (2.3 mL). The resulting mixture was cooled in an ice bath under nitrogen atmosphere, and trifluoromethane sulfonic anhydride (2.7mL, 16 mmol) was added. The reaction mixture was stirred under nitrogen atmosphere at 0°C for 30 min then quenched at 0 °C with water (30 mL) and extracted with DCM (3x 100 mL). The combined organic layers were washed with water (3x 150 mL), 2N HCI (2x250 mL), water (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude of ethyl 2-(3- fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (5.8 g, quant.) as a yellow solid. It was used without further purification.

Step 7: Ethyl 2-(3-fluorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate

A mixture of 2-(3-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3- carboxylate (5.8 g, 12.2 mmol), KF (2.47 g, 42.6 mmol), NaBr (1.33 g, 13 mmol),

cyclopropylboronic acid (1 .7 g, 20 mmol), and Pd(Ph₃P)₄ (0.7 g, 50 mmol) were added toluene (66 mL) and water (1.5 mL). The reaction flask was evacuated for 3 minutes then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hours then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with water (3x 100 mL), brine (150 mL), dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ ethyl acetate = 30/1 -10/1 ) to afford ethyl 2-(3- fluorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate (3.2 g, 71 %) as a brown solid.

Step 8: Ethyl 6-amino-2-(3-fluorophenyl)-5-cyclopropylbenzofuran-3-carboxylate To a solution of ethyl 2-(3-fluorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3- carboxylate (3.2 g, 8.67 mmol) in ethyl acetate (100 mL) was added 10% palladium on activated carbon (0.73 g), 1 N HCI solution (1 mL), and stirred with under 0.4 MPa of hydrogen at room temperature for 8 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give the amine as a brown solid (3.3 g, 1 12 %).

Step 9: Ethyl 5-cyclopropyl-2-(3-fluorophenyl)-6-(N- (methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate

To a solution of ethyl 6-amino-2-(3-fluorophenyl)-5-cyclopropylbenzofuran-3- carboxylate (2.94 g, 8.673 mmol) in dry dichloromethane (60 mL) at -15 °C under N₂ atmosphere was added dry TEA (3.23 mL, 21 .68 mmol) then methanesulfonyl chloride (2.36 mL, 30.356 mmol) was added drop wise. The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3^*60 mL). The organic layers were combined, dried over Na₂S0₄, filtered and evaporated under vacuum to afford the crude of 5-cyclopropyl-2-(3- fluorophenyl)-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate (5.3 g, quant.). This material was used without further purification. Step 10: 5-Cyclopropyl-2-(3-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid

Potassium hydroxide(7.3 g, 130 mmol) was added to a solution of 5-cyclopropyl-2-(3- fluorophenyl)-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate (4.3 g, 8.68 mmol) dissolved in ethanol(31 mL) and water(15.5 mL) under nitrogen atmosphere. The reaction was refluxed for 1 hour, and then concentrated. The remaining solid was dissolved in water, and the solution was acidified with 1 N HCI (120 mL) until a precipitate formed. The solid was filtered and then dried to afford the desired product (3.7 g, quant.). This material was used without further purification. Step 11: 5-Cyclopropyl-2-(3-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide

5-Cyclopropyl-2-(3-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (3.38 g, 8.68 mmol) was stirred in dry N,N-dimethylformamide (15 mL) at 21 °C , then DIPEA (2.47 g, 19.1 mmol) and HATU (3.98 g, 10.414 mmol) were added . After stirred 15 minutes, 2M methylamine (17.3 mL, 34.7 mmol) in THF was added drop wise. The mixture was stirred for another 2 hours then added water (30ml). The mixture solution was extracted with EA(3^*50 mL), washed with water (2^*100 mL), dried and concentrated to afford 5-cyclopropyl- 2-(3-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide as a brown solid (2.8 g, 80 %).

Step 12: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-2-(3-fluorophenyl)-5-cyclopropyl- N-methylbenzofuran-3-carboxamide

Potassium carbonate (0.82 g, 5.97 mmol), Kl (0.33 g, 1 .99 mmol) and (2- Bromomethylallyloxymethyl)benzene (0.96 g, 3.98 mmol) were added to a solution of 5- Cyclopropyl-2-(3-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (0.8 g, 1.99 mmol) in dry DMF (10 mL) under nitrogen. The reaction mixture was stirred at room temperature for 0.5 hour, diluted with water (30 mL), and filtered. The residue was dissolved in EA, dried and concentrated in vacuo to afford the crude product. It was purified by column chromatography (first EA/PE=1 :10, then EA PE=1 :2) to give 6-(N-(2- (benzyloxymethyl)allyl)methylsulfonamido)-2-(3-fluorophenyl)-5-cyclopropyl-N- methylbenzofuran-3-carboxamide (0.8 g, 71 %) as a brown solid.

Step 13: 6-(N-(3-(benzyloxy)-2-((4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-2-(3-fluorophenyl)-5-cyclopropyl-N-methylben carboxamide

Carbonylbis(triphenylphosphine)rhodium(l) chloride (98.1 mg, 0.142 mmol) and 6-(N- (2-(benzyloxymethyl)allyl)methylsulfonamido)-2-(3-fluorophenyl)-5-cyclopropyl-N- methylbenzofuran-3-carboxamide (800 mg, 1.42 mmol) were dissolved in THF (12 mL) under nitrogen atmosphere. Pinacolborane (0.91 g, 7.1 mmol) was added and the mixture was stirred for 24 hours. The solvent was removed in vacuo and the crude residue was purified by column chromatography (first EA PE=1 :5, then EA/PE=1 :2) to give 6-(N-(3-(benzyloxy)-2- ((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl)propyl)methylsulfonamido)-2-(3- fluorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.96 g, 98% yield).

Step 14: 2-( 3-fluorophenyl)-5-cyclopropyl-6-(N-( ( 2-hydroxy- 1, 2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-2-(3-fluorophenyl)-5-cyclopropyl-N-methylbenzofuran-3- carboxamide(0.96 g, 1.39 mmol) was dissolved in THF (15 mL). Palladium on activated carbon (10%, 330 mg) was added and the mixture was stirred under hydrogen (40 Psi) at room temperature for 48 hours. The mixture was filtered and concentrated. The residue was dissolved in THF (15 mL) and treated with 5 N HCI (1 .95 mL) and PS-benzene boronic acid (2.7 g, 6.95 mmol). The mixture was stirred for 3 hours, then filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC to give 2-(3-fluorophenyl)-5- cyclopropyl-6-(N-((2-hydroxy-1 ,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N- methylbenzofuran-3-carboxamide (95 mg, 14% yield)as a white solid. ¹ H NMR (300MHz, CD₃OD) 5 =7.75(m,3H), 7.55(q, 1 H), 7.23(m, 1 H), 7.1 1 (s, 1 H),3.84 (m,4H),3.09(s,3H), 2.95(s,3H),2.48(m,2H), 1 .1 1 (m,2H),0.95(m,2H), 0.71 (m,2H) LCMS( m/z) ES+=501 (M+1 )

Example 36

5-cvclopropyl-2-(3-fluorophenyl)-6-(N-((1 -hvdroxy-1 ,3-dihvdrobenzorciri .2loxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: methyl 5-((N-(5-cyclopropyl-2-(3-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-iodobenzoate

A solution of 5-cyclopropyl-2-(3-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (0.8 g, 1 .99 mmol), methyl 5-(bromomethyl)- 2-iodobenzoate (1 g, 2.82 mmol, U25284/82/1 ), potassium carbonate (0.823 g, 5.97 mmol) and Kl (0.33 g, 1 .99 mmol) in dry DMF (10 ml) was heated at 80 ^°C for 0.5 h under nitrogen atmosphere. The reaction solution was quenched with water (20 mL). After the filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford methyl 5-((N-(5-cyclopropyl-2-(3-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-iodobenzoate (0.65g, 0.961 mmol, 50%) as a brown solid.

Step2: methyl 5-((N-(5-cyclopropyl-2-(3-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)benzoate

A solution of methyl 5-((N-(5-cyclopropyl-2-(3-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-iodobenzoate (650mg, 0.961 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (97 mg, 0.096 mmol), bis(pinacolato)diboron (0.366 g, 1 .44 mmol) and potassium acetate (283 mg, 2.883 mmol) in anhydrous DMF (15 ml) was heated at 100 °C for 15 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography to afford methyl 5-((N-(5-cyclopropyl-2- (3-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (0.3 g, 0.443 mmol, 46%) as a yellow solid. Step3: 5-cyclopropyl-2-(3-fluorophenyl)-6-(N-( (1 -hydroxy- 1, 3-dihydrobenzo[c][ 1, 2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

To a solution of methyl 5-((/V-(5-cyclopropyl-2-(3-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (300 mg, 0.443 mmol ) in THF (15 ml), was added LiBH4 (2M in THF, 0.443 ml, 0.886 mmol) at 0 °C. The reaction solution was stirred at room temperature for 2 hours and then poured into water. The solution was extracted with EtOAc and the separated organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with reverse phase HPLC to afford 5-cyclopropyl-2-(3- fluorophenyl)-6-(N-((1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (93.8 mg, 0.171 mmol, 38.6%) as a white solid. ¹H NMR(300MHz, Methanol_d₄) δ: 7.71 - 7.48 (m, 5 H), 7.30 - 7.18 (m, 3 H), 7.03 (s, 1 H), 5.06 - 4.87 (m, 4 H), 3.18 (s, 3 H), 2.95 (s, 3 H), 2.23 (m, 1 H), 0.98 - 0.31 (m, 4 H). LCMS (m/z, ES⁺)= 548.9 (M+1 ).

Example 37

2-(4-chlorophenyl)-5-cvclopropyl-6-(/\/-((1-hvdroxy-1 ,3-dihvdrobenzo[cl[l2loxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: methyl 5-((N-(5-cyclopropyl-2-(4-chlorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-iodobenzoate

A solution of 5-cyclopropyl-2-(4-chlorophenyl)-/V-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (0.8 g, 1.91 mmol), methyl 5-(bromomethyl)- 2-iodobenzoate (1 g, 2.82 mmol, U25284/82/1 ), potassium carbonate (0.791 g, 5.73 mmol) and Kl (0.317 g, 1.91 mmol) in dry DMF (10 ml.) was heated at 80 °C for 30 minutes under nitrogen atmosphere. The reaction solution was quenched with water (30ml_). After the filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified by column chromatography to afford methyl 5-((N-(5-cyclopropyl-2-(4-chlorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-iodobenzoate (0.75 g, 1 .08 mmol, 57%) as a brown solid. Step 2: methyl 5-((N-(5-cyclopropyl-2-(4-chlorophenyl)-3-(methylcarbamoyl)benzofura yl)methylsulfonamido)methyl)-2-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)benzoate

A solution of methyl 5-((/V-(5-cyclopropyl-2-(4-chlorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-iodobenzoate (750mg, 1.08 mmol), bis(pinacolato)diboron (0.412 g, 1.62 mmol), potassium acetate (318 mg, 3.24 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (1 12 mg, 0.1 1 mmol) in dry DMF (15 mL) was heated at 100 °C overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography to afford methyl 5-((/V-(5-cyclopropyl-2-(4- chlorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (0.39 g, 0.563 mmol, 36%) as a brown solid.

Step3: 5-cyclopropyl-2-(3-chlorophenyl)-6-(N-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol- 5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

A solution of methyl 5-((/V-(5-cyclopropyl-2-(4-chlorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (390 mg, 0.563 mmol ) in THF (15 mL) was treated with LiBH₄ (2M in THF, 0.563 mL, 1.126 mmol) at 0 °C. The resulting solution was stirred at room temperature for 1 .5 hours and then poured into water. The solution was extracted with EtOAc and the separated organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with preparatory HPLC to afford 5- cyclopropyl-2-(4-chlorophenyl)-6-(/\/-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide (90.4 mg, 0.16 mmol, 28%) as a white solid. ¹H NMR(300MHz, Methanol_d₄) δ: 7.86 - 7.83 (m, 2 H), 7.61 - 7.50 (m, 4 H), 7.30 - 7.22 (m, 2 H), 7.03 (s, 1 H), 5.51 - 4.87 (m, 4 H), 3.18 (s, 3 H), 2.95 (s, 3 H), 2.23 (m, 1 H), 0.98 - 0.31 (m, 4 H). LCMS( m/z, ES⁺)= 564.7(M+1 ).

Example 38

5-cvclopropyl-2-(3,4-difluorophenyl)-6-(N-((1-hvdroxy-1 ,3-dihvdrobenzorciri ,2loxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: Methyl 5-((N-(5-cyclopropyl-2-(3 - ifluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-iodobenzoate

5-cyclopropyl-2-(3,4-difluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (0.75g, 1.8 mmol) was dissolved in acetonitrile (40 ml) under nitrogen, then added methyl 5-(bromomethyl)-2-iodobenzoate (0.766 g, 2.16 mmol) and potassium carbonate (0.745 g, 5.4 mmol). The reaction mixture was heated to 70°C and stirred until reaction was completed by TLC. Diluted with EtOAc (50 ml) / water (50 ml), extracted with EtOAc (3x50 ml), washed with brine (100 ml), back extracted, dried over sodium sulfate, and flashed (EtOAc : hex = 1 : 3 ) to give methyl 5-((N-(5-cyclopropyl-2-(3,4-difluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-iodobenzoate (1 .0 g, 83 % ) as a white solid.

Step2: Methyl-5-((N-(5-cyclopropyl-2-(3,4-difluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)benzoate

Methyl-5-((N-(5-cyclopropyl-2-(3,4-difluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-iodobenzoate (1 g, 1.4 mmol) was dissolved in anhydrous dioxane (25 ml) under nitrogen, then added HBPin (5.37g, 42 mmol), triethylamine (1 g, 9.8 mmol), dicyclohexylphosphinobiphenyl (52.5mg, 0.14mmol) were added. The mixture was immersed in a 100°C oil bath and PdOAc₂ (16.8 mg, 0.07 mol) was added quickly. The mixture was stirred until the reaction was complete as observed by LCMS. The mixture was poured into water (50ml), extracted with EtOAc (3x50 ml), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (EtOAc : hex = 1 : 2) to give methyl 5-((N-(5-cyclopropyl-2-(3,4-difluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (850 mg, 85 %) as a white solid.

Step3: 5-cyclopropyl-2-(3,4-difluorophenyl)-6-(N-( ( 1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide

LiBH4 (2M in THF, 1 .2 ml, 2.4 mmol) was added slowly to a solution of methyl 5-((N-

(5-cyclopropyl-2-(3,4-difluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (850mg, 1.4 mmol ) in THF (15 ml) at -5 °C. The mixture was stirred for 15 minutes and poured into ice/water (20 ml), extracted with EtOAc (3^*20 ml), washed with brine (30 ml), dried over sodium sulfate, concentrated and purified by preparatory HPLC to give 5- cyclopropyl-2-(3,4-difluorophenyl)-6-(N-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (330 mg, 48 %) as a white solid. LCMS {m/z, ES⁺) = 566.9 (M+1 ). ¹H NMR (300 MHz, CD₃OD) δ = 7.86-7.69 (m, 2H), 7.61 (S, 1 H),7.54-7.36 (m,2H), 7.29-7.21 (m, 2H), 7.03 (s, 1 H), 5.04-4.87 (m, 4H), 3.17 (s, 3H), 2.94 (S, 3H), 2.28-2.24 (m, 1 H), 0.99-0.75 (m, 3H), 0.34-0.32 (m, 1 H). Example 39

5-cvclopropyl-6-(N-((1-hvdroxy-1 ,3-dihvdrobenzorciri ,2loxaborol-5- yl)methyl)methylsulfonamido)-N-meth^

carboxamide

Step l: methyl 5-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(4- (trifluoromethyl)phenyl)benzofuran-6-yl)methylsulfonamido

5-cyclopropyl-N-methyl-6-(methylsulfonamido)-2-(4- (trifluoromethyl)phenyl)benzofuran-3-carboxamide (0.5 g, 1.1 mmol) was dissolved in acetonitrile (20 ml) under nitrogen, then added methyl 5-(bromomethyl)-2-iodobenzoate (0.461 g, 1.3 mmol) and potassium carbonate (0.455 g, 3.3 mmol). The reaction mixture was heated to 70°C and stirred until the reaction was observed to be complete by TLC. The mixture was diluted with EtOAc (30 ml) / water (30 ml), extracted with EtOAc (3x30 ml), washed with brine (40 ml), back extracted, dried over sodium sulfate, and flashed (EtOAc : hex = 1 : 3 ) to give methyl 5-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(4- (trifluoromethyl)phenyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-iodobenzoate (0.7g, 87 %) as a white solid.

Step2: Methyl 5-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(4-

(trifluoromethyl)phenyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzoate

Methyl 5-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(4- (trifluoromethyl)phenyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-iodobenzoate

(700mg,0.96 mmol) was dissolved in anhydrous dioxane (20 ml) under nitrogen, and then HBPin (3.48g, 28.6 mmol), triethylamine (680 mg, 6.7 mmol), and

dicyclohexylphosphinobiphenyl (35 mg, 0.1 mmol) were added. The mixture was immersed in a 100°C oil bath and PdOAc₂ (1 1.2 mg, 0.05 mol) was added quickly. The mixture was stirred until the reaction was judged complete by LC-MS, poured into 20ml water, and extracted with EtOAc (3x30 ml). The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (EtOAc : hex = 1 : 2) to give methyl 5-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(4-

(trifluoromethyl)phenyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoate (650 mg, 89 %) as a white solid.

Step3: 5-cyclopropyl-6-(N-( ( 1-hydroxy-1, 3-dihydrobenzo[c][ 1, 2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methyl-2-(4-(trifluoromethyl)phenyl)benz

carboxamide

LiBH₄ (2M in THF, 0.9 ml, 1 .8 mmol) was added slowly to a solution of methyl 5-((N-

(5-cyclopropyl-3-(methylcarbamoyl)-2-(4-(trifluoromethyl)phenyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (650mg, 0.9 mmol ) in THF (15 ml) at -5 °C. The mixture was stirred for 15 minutes and poured into ice/water (20 ml), extracted with EtOAc (3^*20 ml), washed with brine (30 ml), dried over sodium sulfate, concentrated and purified by reverse phase HPLC to give 5- cyclopropyl-6-(N-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3- carboxamide (200 mg, 37 %) as a white solid.

LCMS {m/z, ES⁺) = 598.8 (M+1 ). ¹H NMR (300 MHz, CD₃OD) δ =8.03- 8.00 (d, 2H), 7.80- 7.77 (d, 2H), 7.63-7.51 (m, 2H), 7.30-7.22 (m, 2H), 7.04 (s, 1 H), 5.03-4.88 (m, 4H), 3.18 (s, 3H), 2.94 (S, 3H), 2.29-2.22 (m, 1 H), 1.00-0.76 (m, 3H), 0.35-0.31 (m, 1 H).

Example 40

5-cvclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((1 -hvdroxy-1 ,3- dihvdrobenzorciri ,21oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide

Step 1: ethyl 3-(4-bromophenyl)-3-oxopropanoate

A solution of 4-chlorobenzoic acid (40.0 g, 0.199 mol) in DCM (300 mL) was added oxalyl chloride (27 mL, 0.31 1 mol) then DMF (0.5 mL) was added drop wise. The reaction mixture was refluxed for 2 hrs. The resulting clear solution was concentrated in vacuo. The acid chloride was obtained as yellow liquid. A solution of ethyl potassium malonate (38g, 0.222 mol) in MeCN (550 mL) was added TEA (76 mL) and cooled in an ice-salt bath, MgCI₂ (28.4 g, 0.299 mol) was added, and the resulting mixture was stirred at that temperature for 3 hrs. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2 N HCI (600 mL). This mixture was stirred in the ice bath for 1 .5 hrs then transferred to a separatory funnel and extracted with EA (3x200 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate (450 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product ethyl 3-(4-bromophenyl)-3-oxopropanoate ( 48.4 g, 89 %). It was used without purification for further step.

Step 2: ethyl 2-(4-bromophenyl)-5-hydroxybenzofuran-3-carboxylate

Zinc chloride (26.8 g, 0.197 mol) was stirred in anhydrous ethanol (75 mL) then heated to 95 °C (reflux) under nitrogen atmosphere using oven dried glassware. Ethyl 4- bromobenzoylacetate (50 g, 0.184 mol) was added as a single portion followed by drop wise addition of a solution of benzoquinone (21.5 g, 0.199 mol) in anhydrous MTBE (550 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155 °C and an internal temperature of 75-95 °C maintained throughout most of the addition. Half way through the addition more anhydrous ethanol (75 mL) was added because the reaction mixture became thick and a loss of some of the original volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried and evaporated under vacuum. The residual brown solid was slurried in warm

dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give the benzofuran (26.5 g, 39 %).

Step 3: ethyl 2-(4-bromophenyl)-5-isopropoxybenzofuran-3-carboxylate

Ethyl 2-(4-bromophenyl)-5-hydroxybenzofuran-3-carboxylate (26.5 g, 0.073 mol) in NMP (300 mL) was treated with 2-iodopropane (22 mL) and then cesium carbonate (47.8 g, 0.147 mol) was added. The reaction mixture was stirred in a 60 °C oil bath for 4 hrs then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 min. This mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound ethyl 2-(4-bromophenyl)-5- isopropoxybenzofuran-3-carboxylate (30 g, 102 %).

Step 4: ethyl 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-bromophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (30 g, 0.073 mol) was dissolved in chloroform (60 mL) and the resulting solution was cooled in an ice bath. Nitric acid (49 mL) was also dissolved in chloroform (60 mL) and cooled in an ice bath. The acid solution was added drop wise to the solution of compound ethyl 2-(4-bromophenyl)-5- isopropoxybenzofuran-3-carboxylate over 0.5 hour, and the reaction mixture was then stirred at 0°C for 0.5 hour. The reaction mixture was then diluted with water (100 mL) , and the layers were separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil .It was slurried in 15 mL MTBE then filtered to obtained ethyl 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as an orange solid (14.5 g, 44.6 %).

Step 5: ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (13.2 g, 29.45 mmol) was dissolved in toluene (80 mL) . Di-tert-butyl(2',4',6'-triisopropylbiphenyl-2- yl)phosphine (2 g, 4.712 mmol), potassium phosphate (12.5 g, 58.9 mmol) and palladium diacetate (529 mg, 2.356 mmol) were added. The resulting solution was stirred under nitrogen at 100 °C overnight. The reaction was cooled to room temperature and washed with water (3^*50 mL) .The combined solution was dried then concentrated to obtain the crude product. It was purified by recrystallization with EtOH (150 mL) to afford the pure product as a light yellow solid (1 1.1 g, 79%).

Step 5: Ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (1 1.1 g, 23.15mmol) was dissolved in anhydrous DCM (150 mL) and cooled in an ice bath under an atmosphere of nitrogen. Boron trichloride (35 mL, 34.7mmol) was added over 20 minutes. After the reaction was complete, the mixture was quenched by pouring into an ice/water mixture. The reaction mixture was poured into the ice/water mixed with DCM. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give compound Ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (10.4 g, quant. yield). Step 6: Ethyl 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran- 3-carboxylate

A solution of ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzofuran-3- carboxylate (10.4 g, 23.15 mmol) and DMAP (0.292 g, 2.39 mmol) in anhydrous DCM (350 mL) and anhydrous TEA (4.85 mL) in an ice bath under nitrogen was added trifluoromethane sulfonic anhydride (5.68mL, 34.4 mmol). The reaction mixture was stirred under nitrogen at 0°C for 30 minutes and then quenched at 0 °C with water (200 mL) and extracted with DCM (3x200 mL). The combined organic layers were washed with water (3x600 mL), 2N HCI (2^*300 mL), water (300mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. Ethyl 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5-

(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (13.25 g, 100 %) was obtained as a yellow solid. It was used without further purification.

Step 7: Ethyl 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-nitrobenzofuran-3-carboxylate A mixture of ethyl 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5-

(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (13.25 g, 23.27 mmol), KF (4.73 g, 81 .45 mmol), NaBr (2.54 g, 24.67 mmol), cyclopropylboronic acid (3.0 g, 34.91 mmol), and Pd(Ph₃P)₄ (1.34 g, 1 .16 mmol) were added toluene (130 mL) and water (3 mL). The reaction flask was evacuated for 3 minutes and then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hours then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (150 mL), washed with water (3x200 mL), brine (200 mL), dried with anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified by column chromatography (first PE/EA=4/1 , then PE/EA=1/1 ) to afford ethyl 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-nitrobenzofuran-3-carboxylate as a yellow solid (8.4 g, 78 %).

Step 8: Ethyl 6-amino-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)benzofuran-3-carboxylate To a solution of ethyl 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-nitrobenzofuran- 3-carboxylate (8.4 g, 18.2 mmol) in ethyl acetate (400 mL) was added 10% palladium on activated carbon (1 .56 g) and 1 N HCI solution (2.3 mL). The mixture was stirred under 0.4 MPa of hydrogen at room temperature for 8 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give the amine as a brown solid (8 g, 100 %). Step 9:

ethyl 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N- (methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate To a solution of ethyl 6-amino-5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)benzofuran-3-carboxylate (8 g, 18.54 mmol) in dry dichloromethane (180 ml.) at -15 °C under N₂ atmosphere was added dry TEA (6.91 ml_, 46.35 mmol) and then methanesulfonyl chloride (5.05 ml_, 64.9 mmol) drop wise. The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100ml_) and extracted with DCM (3x150ml_). The organic layers were combined, dried with NaS04, filtered and evaporated under vacuum to afford ethyl 5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3- carboxylate as a brown solid (9.5 g, 87 %).

Step 10: 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(methylsulfonamido)benzofuran-3- carboxylic acid

Potassium hydroxide(13.6 g, 243 mmol) was added to a solution of the ethyl 5- cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N- (methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate in ethanol(70 ml.) and water(35 ml.) under a nitrogen atmosphere. The reaction was refluxed for 1 hour, and then concentrated in vacuo. The remaining solid was dissolved in water, and the solution was acidified with 2 N HCI (141 ml.) until a precipitate formed. The solid was filtered and then dried to afforded 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6- (methylsulfonamido)benzofuran-3-carboxylic acid as a white solid (9 g, quant, yield). This material was used without further purification.

Step 11: 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-

(methylsulfonamido)benzofuran-3-carboxylic acid (9.9 g, 20.56 mmol) in dry DMF (50 ml.) was treated with DIPEA (5.86 g, 45.23 mmol) and HATU (9.42 g, 24.67 mmol) at 20 °C. After

15 minutes, 2 M methylamine in THF (41 .12 ml_, 82.24 mmol) was added drop wise and the mixture was stirred for another 2 hours and then diluted with water (200ml). The mixture was extracted with EA (3^*250 ml_), washed with water (2^*200 ml_), dried and concentrated to afford 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide as a reddish brown thick oil (10 g, 98 %).

Step 12: methyl 5-((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methyl)methylsulfonamido)methyl)-2-iodobenzoate

Potassium carbonate(418 mg, 3.03 mmol), Kl (168 mg, 1 .01 mmol) and methyl 5- (bromomethyl)-2-iodobenzoate (717 mg, 2.02 mmol) were added to a solution of 5- cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-(methylsulfonamido)benzofura carboxamide (0.5 g, 1.01 mmol) in dry DMF (8 ml.) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, diluted with water (30 ml_), and filtered. The residue was dissolved in EA, dried, concentrated in vacuo and purified by column chromatography (first EA PE=1 :10, then EA PE=1 :2) to give methyl 5-((N-((5- cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-iodobenzoate as a brown solid (365 mg, 46 %).

Step 13: methyl 5-((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methyl)methylsulfonamido)methyl)-2-(4,4, 5, 5-tetramethyl-

1, 3, 2-dioxaborolan-2-yl)benzoate

Methyl 5-((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methyl)methylsulfonamido)methyl)-2-iodobenzoate (365 mg, 0.466 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (237 mg, 0.933 mmol) and KOAc (137 mg, 1.4 mmol) in 1 ,4-dioxane (20 ml.) under nitrogen atmosphere were treated with Pd(dppf)₂CI₂(54 mg, 0.047 mmol) and the mixture was stirred for 24 hours.

The solvent was removed in vacuo and the crude residue was purified by column

chromatography (first EA/PE=1 :5, then EA PE=1 :2) to give methyl 5-((N-((5-cyclopropyl-2-(4-

(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate

(0.345 g, 94 %).

Step 14: 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide

Methyl 5-((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methyl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoate (0.345 g, 0.449 mmol) in THF (15 ml.) was treated drop wise with 2 M LiBH₄ in THF (0.449 ml_, 0.898 mmol) at 0 °C. The mixture was stirred for 1 .5 hours. Then the reaction was quenched by adding a solution of water/EA (1 :1 , 25 ml_). The mixture was extracted with EA (3x20 ml.) and the combined organic layers were dried and concentrated in vacuo. The residue was purified by pre-HPLC to afford 5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-6-(N-((1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (61 mg, 20 %) as a white solid. ¹H NMR (300MHz, CDCI3) δ =7.86-7.83(d,2H),7.56-7.52(t,2H), 7.39-7.00(m,9H), 4.99(s,4H), 3.16(s,3H), 2.92(s,3H), 2.23(m,1 H), 0.98(m, 1 H), 0.92-0.88(m,2H), 0.35- 0.33(m, 1 H). LCMS( m/z) ES+=641 .2(M+1 ) Example 41

(±)-5-cvclopropyl-2-(4-fluorophenyl)-6-[[(1-hvdroxy-3-methyl-1 ,3-dihvdro-2, 1-benzoxaboro yl)methyll(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

Step 1: 2-bromo-N,5-dimethyl-N-(methyloxy)benzamide

A solution of 2-bromo-5-methylbenzoic acid (9.23 g, 42.9 mmol), N,0- dimethylhydroxylamine (5.23 g, 53.7 mmol), EDC (10.70 g, 55.8 mmol), HOBT (8.54 g, 55.8 mmol), and triethylamine (1 1 .96 mL, 86 mmol) in dichloromethane (300 mL) was maintained with stirring overnight. The mixture was poured into saturated sodium bicarbonate and the organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and taken to a residue under reduced pressure. The residue was purified by column

chromatography to afford 2-bromo-N,5-dimethyl-N-(methyloxy)benzamide (10.45 g, 40.5 mmol, 94 % yield) as a clear oil. LCMS {m/z, ES⁺) = 259 (M+H)

Step 2: 1-(2-bromo-5-methylphenyl)ethanone

A solution of 2-bromo-N,5-dimethyl-N-(methyloxy)benzamide (10.45 g, 40.5 mmol) in tetrahydrofuran (300 mL) was treated with 3.0M MeMgBr (THF) (40.5 mL, 121 mmol) and maintained with stirring at room temperature for 6 hours. The mixture was cooled to 0°C, quenched via drop wise addition of saturated ammonium chloride, and diluted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 1 -(2-bromo-5- methylphenyl)ethanone (7.46 g, 35.0 mmol, 86 % yield) as a yellow oil. LCMS {m/z, ES⁺) = (M+H)

Step 3: 1-(2-bromo-5-methylphenyl)ethanol

A solution of 1-(2-bromo-5-methylphenyl)ethanone (7.2 g, 33.8 mmol) in methanol (100 mL) was maintained with stirring at 0°C and treated portion wise with sodium borohydride (3.20 g, 84 mmol). The mixture was maintained with stirring for 3 hours and diluted with ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford 1-(2-bromo-5-methylphenyl)ethanol (6.06 g, 28.2 mmol, 83 % yield) as a clear oil. ¹H NMR (DMSO-d₆) δ: 7.33 - 7.47 (m, 2H), 6.98 (d, J = 8.0 Hz, 1 H), 5.35 (d, J = 4.1 Hz, 1 H), 4.79 - 4.98 (m, 1 H), 2.28 (s, 3H), 1 .27 (d, J = 6.4 Hz, 3H). Step 4: 1-bromo-4-methyl-2-(1-{[(methyloxy)methyl]oxy}ethyl)benzene

A solution of 1-(2-bromo-5-methylphenyl)ethanol (6.065g, 28.2 mmol) in

dichloromethane (150 mL) was treated with DIPEA (19.70 mL, 1 13 mmol) and MOM-CI (4.28 mL, 56.4 mmol) and maintained at room temperature with stirring for 3 hours. The mixture was poured into saturated ammonium chloride and the organic layer was mixed with celite, concentrated to a residue, and purified by column chromatography to afford 1-bromo-4- methyl-2-(1 -{[(methyloxy)methyl]oxy}ethyl)benzene (3.30 g, 12.73 mmol, 45.2 % yield) as a clear oil. ¹H NMR (DMSO-d₆) δ: 7.44 (d, J = 8.2 Hz, 1 H), 7.32 (s, 1 H), 6.96 - 7.13 (m, 1 H), 4.96 (d, J = 6.4 Hz, 1 H), 4.59 (d, J = 6.8 Hz, 1 H), 4.44 (d, J = 6.6 Hz, 1 H), 3.26 (s, 3H), 2.29 (s, 3H), 1 .34 (d, J = 6.4 Hz, 3H).

Step 5: 1-bromo-4-(bromomethyl)-2-(1-{[(methyloxy)methyl]oxy}ethyl)benzene

A solution of 1-bromo-4-methyl-2-(1 -{[(methyloxy)methyl]oxy}ethyl)benzene (1.5 g, 5.79 mmol), NBS (1.082 g, 6.08 mmol), and AIBN (0.048 g, 0.289 mmol) in carbon tetrachloride (35 mL) was maintained with stirring at 80°C for 5 hours. The mixture was cooled to room temperature, poured into saturated sodium bicarbonate, and diluted with additional dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and passed through a plug of silica, and used crude in the subsequent chemical transformation (1 .27 g, 2.254 mmol, 38.9 % yield). Step 6: 6-[{[4-bromo-3-(1 -

{[(methyloxy)methyl]oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino

fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (950 mg, 2.361 mmol), 1 -bromo-4-(bromomethyl)-2-(1- {[(methyloxy)methyl]oxy}ethyl)benzene (1 197 mg, 3.54 mmol, crude residue from Step 5), and potassium carbonate (652 mg, 4.72 mmol) in acetonitrile (25 mL) was maintained at 80°C with stirring for 3 hours. The mixture was cooled, poured into saturated sodium bicarbonate, and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-[{[4-bromo-3-(1-

{[(methyloxy)methyl]oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (920 mg, 1 .395 mmol, 59.1 % yield) as a white foam. LCMS {m/z, ES⁺) = 661 (M+H)

Step 7: 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-3-methyl-1,3-dihydro-2, 1- benzoxaborol-5-yl)methyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxami

A solution of 6-[{[4-bromo-3-(1 - {[(methyloxy)methyl]oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (200 mg, 0.303 mmol), potassium acetate (1 19 mg, 1 .213 mmol), bis(pinacolato)diboron (135 mg, 0.531 mmol), and

PdCI₂(dppf)-CH₂CI₂ adduct (18.57 mg, 0.023 mmol) in 1 ,4-dioxane (4 mL) was maintained at 90°C overnight. The mixture was cooled, filtered through celite, and the celite washed with ethyl acetate. The filtrates were concentrated to give a crude residue containing roughly 70% 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[{[3-(1-{[(methyloxy)methyl]oxy}ethyl)-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide. The crude residue (214 mg, 0.303 mmol) in tetrahydrofuran (5 mL) was treated with 5. ON HCI (aq) (3.03 mL, 15.15 mmol) and polymer supported benzene boronic acid (582 mg, 1 .515 mmol) and maintained at 65°C for 3 hours. The mixture was cooled, filtered through celite, and the filtrates diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 5-cyclopropyl-2-(4- fluorophenyl)-6-[[(1-hydroxy-3-methyl-1 ,3-dihydro-2, 1 -benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide (65 mg, 0.1 16 mmol, 38.1 % yield) as a yellow foam. ¹ H NMR (DMSO-d₆) δ: 8.76 (s, 1 H), 8.09 (br. s., 1 H), 7.92 (dd, J = 8.8, 5.5 Hz, 2H), 7.54 - 7.70 (m, 2H), 7.33 (t, J = 9.0 Hz, 2H), 7.23 (d, J = 6.4 Hz, 2H), 6.99 (s, 1 H), 5.12 (q, J = 6.4 Hz, 1 H), 4.92 (br. s., 2H), 3.04 (s, 3H), 2.82 (d, J = 4.5 Hz, 3H), 2.17 - 2.26 (m, 1 H), 1.30 (d, J = 6.4 Hz, 3H), 0.68 - 0.98 (m, 3H), 0.36 (m, 1 H). LCMS {m/z, ES⁺) = 563 (M+H)

Example 42

5-cvclopropyl-6-(N-((7-fluoro-1-hvdroxy-1 ,3-dihvdrobenzorciri ,2loxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: 2-amino-3-fluoro-5-methylbenzoate

Pd(OAc)₂ (880 mg, 3.92 mmol), DPPF (3.26 g, 5.88 mmol) and Et₃N (2.2 g, 20.58 mmol) were added to a solution of 2-bromo-6-fluoro-4-methylbenzenamine (4.0 g, 19.6 mmol) in DMSO (132 mmol) and MeOH (87 mmol). The mixture was heated to 80 °C under 1.5 M Pa of carbon monoxide and stirred for 16 hours. The mixture was cooled to room temperature and filtered. The mixture was diluted with EA (200 mL), washed with water (200 mL), and brine (100 mL), dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (EA:PE = 1 :20) to give methyl 2-amino-3-fluoro-5- methylbenzoate (2.7 g, 75 %).

Step 2: methyl 2-bromo-3-fluoro-5-methylbenzoate

Methyl 2-amino-3-fluoro-5-methylbenzoate was dissolved in MeCN (20mL), after cooled to 0 °C, 14.8 mLof HBr (47% in water) was added dropwise over 10 minutess, then NaN0₂ (910 mg, 13.2 mmol) in water (2mL) was added dropwise over 1 h. After addition, The solution was stirred for 5 mins, and CuBr (2.01 mg, 13.8 mmol) was added portionwise over 30 mins. The mixture was heated to 70 °C for 1 h, then cooled to 0 °C, water was added (20 mL) and the mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with cooled water (70 mL) and dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give methyl 2-bromo-3-fluoro-5-methylbenzoate (1 .39 g, 46 %).

Step 3: methyl 2-bromo-5-(bromomethyl)-3-fluorobenzoate

Methyl 2-bromo-3-fluoro-5-methylbenzoate (1.39 g, 5.63 mmol), benzoyl peroxide (72.6 mg, 0.3 mmol) and N-bromosuccinimide (1.1 g, 6.2 mmol) were dissolved in 30 mL of CCI₄ and heated to reflux for 2 days. The reaction was cooled and concentrated in vacuo. The residue was purified by column chromatography (PE/EA = 20 : 1 ) to give methyl 2- bromo-5-(bromomethyl)-3-fluorobenzoate (1.9 g, 104 %).

Step 4: Methyl 2-bromo-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-3-fluorobenzoate

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (500 mg, 1 .24 mmol), Kl (10.3 mg, 0.06 mmol) and K₂C0₃ (513 mg, 3.72 mmol) in dry DMF (15 mL) was treated with methyl 2- bromo-5-(bromomethyl)-3-fluorobenzoate (808 mg, 2.48 mmol) and the reaction was stirred at room temperature under nitrogen for 8 hours. The reaction was diluted with water (30 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (EA:PE = 1 :2) to give methyl 2-bromo-5-((N- (5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-fluorobenzoate (450 mg, 56 %). Step 5: Methyl 5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-fluoro-2-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2- yl)benzoate

Methyl 2-bromo-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-3-fluorobenzoate (450 mg, 0.69 mmol) was dissolved in dioxane (20 ml.) under a nitrogen atmosphere.

Bis(pinacolato)diboron (353 mg, 1.39 mmol), potassium acetate (196 mg, 2.07 mmol) and 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride (80 mg, 0.07 mmol) were added and the mixture was stirred at 100 °C overnight. The cooled reaction mixture was poured into water (40 ml.) and extracted with EtOAc (3x40 ml_). The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column

chromatography (eluting with 0-50% ethyl acetate in petroleum) to give methyl 5-((N-(5- cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-fluoro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate as a white solid (340 mg, 71 %).

Step 6: 5-cyclopropyl-6-(N-((7-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LiBH₄ (2M in THF, 0.74 ml, 1.47 mmol) was added slowly to a solution of methyl 5- ((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-fluoro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (340mg, 0.49 mmol ) in THF (15 ml) at -5 °C, then warmed to room temperature and stirred for 3 hours. The mixture was poured into ice/water (20 ml), extracted with EtOAc (3^*20 ml), washed with brine (30 ml), and dried over sodium sulfate. Concentration and purification by reverse phase HPLC gave 5-cyclopropyl-6-(N-((7-fluoro-1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-5-yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (50 mg, 18 %) as a white solid. LCMS (m/z) ES⁺ = 567.2 (M+1 ). ¹H NMR (300 MHz, CD₃OD) = 7.92-7.88 (m, 2H), 7.62 (S, 1 H), 7.27-7.21 (m, 2H), 7.10-7.89 (m, 3H), 5.04-4.92 (m, 4H), 3.17 (s, 3H), 2.92 (S, 3H), 2.28-2.24 (m, 1 H), 1 .03-0.85 (m, 3H), 0.41-0.35 (m, 1 H)

Example 43 5-cvclopropyl-6-(N-((4-fluoro-1-hvdroxy-1 ,3-dihydrobenz

yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-c^

Step 1: 6-bromo-2-fluoro-3-iodobenzoic acid

A solution of 4-bromo-2-fluoro-1-iodobenzene (20 g, 66.4 mmol) in THF (60 ml.) was added to a stirred solution of LTMP freshly prepared from TMP (9.8 g, 73.1 mmol) and n-BuLi (45.7 ml_, 73.1 mmol) in THF (100 mL) at -78 °C. After stirring for 40 min at -78 °C, the mixture was saturated with a steam of gaseous of C0₂. The mixture was stirred at -75 °C for 30 min and left to warm to -20 °C, followed by careful hydrolysis with aqueous sulfuric acid (1 .5 M, 100 mL). The water was separated and extracted with with diethyl ether (3^*100 mL). The combined organic layers were concentrated. The residue was filtered and washed consecutively with water, toluene, and hexane. Drying in vacuo afforded 6-bromo-2-fluoro-3- iodobenzoic acid (17 g, 75 %). Step 2: methyl 6-bromo-2-fluoro-3-iodobenzoate

A solution of 6-bromo-2-fluoro-3-iodobenzoic acid (4.5 g, 13.05 mmol) and potassium carbonate (2.7 g, 19.58 mmol) in acetonitrile (45 ml) was treated with iodomethane (2.22 g, 15.66 mmol) and stirred at 60 °C overnight. The mixture was concentrated in vacuo and diluted with EtOAc (100 ml) and water (200 ml). The combined organic layers were washed with brine (60 mlx2), dried over sodium sulfate and purified by column chromatography (EtOAc : PE = 1 : 20 ) to give methyl 6-bromo-2-fluoro-3-iodobenzoate (4.3 g, 92 %) as a colorless oil.

Step 3: methyl 6-bromo-2-fluoro-3-vinylbenzoate

To a solution of methyl 6-bromo-2-fluoro-3-iodobenzoate (4.3 g, 1 1.98 mmol) in dry

DMF (20 ml) under nitrogen was added Pd(PPh₃)₄ (715 mg, 0.62 mmol) and vinyltributyltin (4.5 ml, 14.48 mmol). The mixture was degassed with N₂ for 5 min and heated at 80 °C for 24 h. After cooling, the mixture was partitioned between ether and brine. The organic phase was stirred over 10 % aqueous KF solution for 4 h. The ether layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography (EtOAc : PE = 1 : 20 ) to give methyl 6-bromo-2- fluoro-3-vinylbenzoate (4.0 g, 1 10 %) as a yellow oil. Step 4: methyl 6-bromo-2-fluoro-3-(hydroxymethyl)benzoate

A solution of methyl 6-bromo-2-fluoro-3-vinylbenzoate (4.0 g, 15.2 mmol) in

CH₂Cl2/MeOH (15 ml / 15 ml) was cooled to -78°C and saturated with a stream of gaseous 0₃. The mixture was stirred for 30 min and then NaBH₄ (1 g, 23.9 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 h. Water was added. The solution was extracted with EtOAc (50 ml_^*3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (EtOAc:PE = 1 : 1 ) to give methyl 6-bromo-2-fluoro-3-(hydroxymethyl)benzoate (2.09g, 52 %)

Step 5: methyl 6-bromo-3-(bromomethyl)-2-fluorobenzoate

Methyl 6-bromo-2-fluoro-3-(hydroxymethyl)benzoate (390 mg, 1.48 mmol) was dissolved in DCM (20 ml) and a solution of PPh₃(579 mg, 2.22 mmol) in DCM(5 ml) was slowly added. The mixture was stirred at room temperature for 0.5 h and water was added. The organic layer was separated and washed with brine, dried over sodium sulfate, and purified by column chromatography (EtOAc:PE = 1 : 50 ) to give methyl 6-bromo-3- (bromomethyl)-2-fluorobenzoate (350 mg, 73 %) as a colorless oil. Step 6: Methyl 6-bromo-3-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-fluorobenzoate

Methyl 6-bromo-3-(bromomethyl)-2-fluorobenzoate (350 mg, 1.07 mmol), 5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (430 mg, 1.07 mmol), potassium iodide (9 mg, 0.054 mmol) and potassium carbonate (443 mg, 3.21 mmol) were dissolved in DMF (10 ml). The mixture was stirred at room temperature for 0.5 h and then water was added. The mixture was extracted with EtOAc (20 ml_x3) and washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (EtOAc:PE = 1 : 1 ) to give methyl 6-bromo-3-((N-(5-cyclopropyl-2-(4- fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2- fluorobenzoate (510 mg, 73 %) as a white solid

Step 7: Methyl 3-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluoro-6-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2- yljbenzoate

Methyl-6-bromo-3-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2 -fluorobenzoate (406 mg, 0.71 mmol), PdCI₂(dppf) (25.6 mg, 0.035mmol), B₂PIN₂ (272 mg, 1 .07mmol) and potassium acetate (209 mg, 2.13 mmol) were disolved in dioxane (12 ml) under nitrogen atmosphere. The mixture was stirred at 95 °C for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc (20 ml) / water (20 ml). The organic layer was separated and washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (EtOAc : PE = 1 : 1 ) to give methyl 3-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-fluoro-6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (300 mg, 61 %) as a white solid.

Step 8: 5-cyclopropyl-6-(N-( (4-fluoro- 1-hydroxy-1 ,3-dihydrobenzo[c][ 1, 2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofur^

LiBH₄ (2M in THF) (0.64 ml, 1.28 mmol) was added slowly to a solution of methyl 3- ((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (300 mg, 0.43 mmol ) in THF (10 ml) at 0 °C. After stirring for 2 hours, the mixture was poured into ice/water (20 ml), extracted with EtOAc (20 ml x3), washed with brine, dried over sodium sulfate, concentrated and purified by reverse phase HPLC to give 5- cyclopropyl-6-(N-((4-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (65 mg, 27 %) as a white solid. LCMS {m/z, ES⁺) = 567.1 (M+1 ). 1 H NMR (300MHz, CDCI3) δ =7.93- 7.88(dd,2H),7.61 (s, 1 H), 7.32-7.22(m,4H),7.02(s,1 H), 5.15-4.92(m,4H), 3.19(s,3H),

2.93(s,3H),2.28-2.23(m, 1 H),0.98(m, 1 H),0.82-0.76(m,2H),0.29(m, 1 H) LCMS( m/z)

ES+=567.1 (M+1 )

Example 44 & 45

5-cvclopropyl-2-(4-fluorophenyl)-6-r{r(3S)-1-hvdroxy-3-methyl-1 ,3-dihvdro-2, 1-benzoxaborol-

5-vHmethyl}(methylsulfonyl)aminol-/V-methyl-1 -benzofuran-3-carboxamide & 5-cvclopropyl-2-

(4-fluorophenyl)-6-r{r(3f?)-1 -hvdroxy-3-methyl-1 ,3-dihvdro-2,1 -benzoxaborol-5- yllmethyl}(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

Racemic 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[1-hydroxy-3-methyl-1 ,3-dihydro-2, 1- benzoxaborol-5-yl]methyl}(methylsulfonyl)amino]-/\/-methyl-1-benzofuran-3-carboxamide was resolved using supercritical C0₂ column chromatography with a chiral stationary phase: 40% MeOH/C0₂ 140 bars 40°C 2 mL/min OZ column. Absolute configuration assignments were not made.

First eluting Enantiomer: ¹H NMR (METHANOL-d₄) δ: 7.88 (dd, J = 8.7, 5.4 Hz, 2H), 7.58 (s, 1 H), 7.45 - 7.54 (m, 2H), 7.1 1 - 7.29 (m, 4H), 7.01 (d, J = 13.7 Hz, 1 H), 5.17 (q, J = 6.4 Hz, 1 H), 4.92 - 5.04 (m, 2H), 3.14 (s, 3H), 2.90 (s, 3H), 2.12 - 2.27 (m, 1 H), 1 .24 - 1 .40 (m, 3H), 0.89 - 1 .01 (m, 1 H), 0.63 - 0.83 (m, 2H), 0.20 - 0.35 (m, 1 H). LCMS {m/z, ES⁺) = 563 (M+H).

Second eluting Enantiomer: ¹H NMR (METHANOL-d₄) δ: 7.88 (dd, J = 8.7, 5.4 Hz, 2H), 7.58 (s, 1 H), 7.45 - 7.54 (m, 2H), 7.1 1 - 7.29 (m, 4H), 7.01 (d, J = 13.7 Hz, 1 H), 5.17 (q, J = 6.4 Hz, 1 H), 4.92 - 5.04 (m, 2H), 3.14 (s, 3H), 2.90 (s, 3H), 2.12 - 2.27 (m, 1 H), 1 .24 - 1.40 (m, 3H), 0.89 - 1 .01 (m, 1 H), 0.63 - 0.83 (m, 2H), 0.20 - 0.35 (m, 1 H). LCMS {m/z, ES⁺) = 563 (M+H). Example 46

5-cvclopropyl-2-(4-fluorophenyl)-6-(/\/-(1-(1-hvdroxy-1 ,3-dihvdrobenzorciri2loxaborol-5- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide

Step 1: methyl 2-bromo-5-iodobenzoate

A solution of 2-bromo-5-iodobenzoic acid (2 g, 5.5 mmol), K₂C0₃ (1.5 g, 1 1 mmol) and Mel (0.82 g, 5.8 mmol) in MeCN was heated at 80 °C for 48 h. The reaction mixture was poured into water and then extracted with EtOAc. The separated organic solution was dried over anhydrous Na₂S0_4. The solvent was removed under reduced pressure to afford methyl 2-bromo-5-iodobenzoate (2.2 g, 6.5 mmol, 95 %, yield).

Step 2: methyl 2-bromo-5-vinylbenzoate

A solution of methyl 2-bromo-5-iodobenzoate (1 .5 g, 4.4 mmol), Bu₃SnC₂H₄ (1 .81 g, 5.3 mmol) and Pd(PPh₃)₄ (0.51 g, 0.44 mmol) in DMF (100 mL) was heated at 120 °C for 12 hours. The reaction mixture was diluted with H₂0/EtOAc (100 mL/200 mL). The organic layer was washed with brine (2 x 200 mL) and dried over anhydrous Na₂S0₄. After removal of solvent, the crude product was purified with column chromatography to afford methyl 2- bromo-5-vinylbenzoate (1 .37 g, 5.7 mmol, 95% yield) as a colorless oil. Step 3: 2-bromo-5-( 1-bromoethyl)benzoic acid

A solution of 2-bromo-5-vinylbenzoate (1.37 g, 4.28 mmol) in HBr (48 % aq., 20 mL) was heated at 90 °C for 2 hours and then poured into ice water (200 mL). The aqueous solution was extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 2-bromo-5-(1-bromoethyl)benzoic acid (1 .5 g, 4.7 mmol, 97 % yield) as a yellow oil. Step 4: methyl 2-bromo-5-(1 -bromoethyl)benzoate

A solution of 2-bromo-5-(1-bromoethyl)benzoic acid (1.2 g, 3.92 mmol), K₂CO₃ (1.08 g, 7.84 mmol) and Mel (0.56 g, 3.92 mmol) in MeCN (50 mL) was heated at 80 °C for 24 h.

The reaction mixture was dissolved in water/EA (100 mL/100 mL) and then extracted with

EtOAc (3 x 50 mL). The combined organic layers were washed with H₂0 (2 x 50 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford methyl 2-bromo-5-(1-bromoethyl)benzoate (950 mg,

2.97 mmol, 75 % yield) as a yellow solid.

Step 5: methyl 2-bromo-5-(1-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)benzoate

A solution of methyl 2-bromo-5-(1 -bromoethyl)benzoate (950 mg, 2.97 mmol), 5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1 .18 g, 2.96 mmol) and K₂C0₃ (0.819 g, 5.94 mmol) in MeCN (10 mL) was heated at 80 °C for 3 h. After the reaction solution was cooled to rt, it was poured into water (200 mL) and then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 2-bromo-5-(1 -(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)benzoate (850 mg, 1 .32 mmol, 44 % yield) as a white solid.

Step 7: methyl 5-(1-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzoate

A solution of 2-bromo-5-(1-(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)benzoate (850 mg, 1 .32 mmol), Pd(dppf)CI₂ (78.5 mg, 0.07 mmol), Pin₂B₂ (223 mg, 0.88 mmol) and KOAc (364 mg, 2.64 mmol) in dioxane (50 mL) was heated at 100 °C overnight under nitrogen. The reaction mixture was diluted with ice water (100 mL) and then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 5-(1 -(N-(5- cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (650 mg, 1 .02 mmol, 78 % yield) as a white solid.

Step 8: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-( 1-( 1 -hydroxy-1 ,3- dihydrobenzo[c][1,2]oxaborol-5-yl)ethyl)methylsulfonamido)-N-methylbenzofuran

carboxamide

To a solution of 5-(1 -(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (650 mg, 1 .02 mmo) in THF (10 mL) was added LiBH₄ (2 mL, 2 mmol) at 0 °C and the resulting solution was stirred at room temperature for 2 hours. The reaction solution was poured into ice water (100 mL) and extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with reverse phase HPLC to afford 5-cyclopropyl-2-(4- fluorophenyl)-6-(/V-(1 -(1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide (50 mg, 0.089 mmol, 12 % yield) as a white solid. ¹H NMR (300MHz, CD30D) δ: 7.98-7.89(m,2H), 7.74(s, 1 H),7.74-7.69 (d,0.5H),7.52-7.55(d,0.5H),7.32-7.16(m,3H),7.16-7.09(m,2H),6.89(s, 1 H),5.71-

5.66(m, 1 H),5.14-4.95(m,2H),3.18(s,2H),2.96-2.94(d,3H),2.86(s, 1 H),2.56-2.51 (m,1 H), 1 .78- 1.76(d,2H), 1.58-1 .56(d, 1 H), 1 .17-1.15(m, 1 H),0.85-0.73(1 m, 1.5H),0.49-0.43(m,0.5H),0.17- 0.02(m, 1 H). LCMS (m/z, ES⁺)= 567(M+1 ). Example 47

5-cvclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((2-hvdroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (0.6 g, 1.213 mmol), potassium carbonate (0.502 g, 3.64 mmol), Kl (0.201 g, 1.21 1 mmol) and (2-bromomethylallyloxymethyl)benzene (0.585 g, 2.426 mmol, U25279/75/1 ) in dry DMF (8 ml.) was heated at 40 °C under nitrogen atmosphere for 30 min. The reaction solution was quenched with water (20ml_). After the filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2- (4-(4-fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide (0.49 g, 0.748 mmol, 62%) as a brown oil. Step 2: 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramet yl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N- methylbenzofuran-3-carboxamide

A solution of carbonylbis(triphenylphosphine)rhodium(l) chloride (52 mg, 0.075 mmol), 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide (490 mg, 0.748 mmol) and pinacolborane (479 mg, 3.74 mmol) in THF (15 ml.) was stirred at room temperature under nitrogen atmosphere overnight. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide (0.5 g, 0.638 mmol, 85%) as a brown oil.

Step 3: 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((2-hydroxy-1,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

A solution of 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N- methylbenzofuran-3-carboxamide (0.5 g, 0.639 mmol) and Pd/C (188 mg) in THF (15 ml.) was stirred under hydrogen (40 PSI) at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was dissolved in THF (15 ml.) and treated with HCI (5N aq., 0.9 ml.) and PS-benzene boronic acid (2 g). The suspension was stirred at room temperature overnight, filtered, and concentrated under reduced pressure. The crude residue was purified with reverse phase HPLC to afford 5- cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide as a white solid (75 mg, 0.126 mmol, 20%). ¹ H NMR (300MHz, Methanol- d4) δ: 7.90 - 7.87 (d, 2 H), 7.72 - 7.68 (d, 1 H), 7.21 - 7.06 (m, 7 H), 3.85 - 3.63 (m, 4 H), 3.09 (s, 3 H), 2.96 (s, 3 H), 2.48-2.44 (m, 2 H), 1.1 1 - 0.70 (m, 6 H). LCMS (m/z, ES⁺)= 593.1 (M+H). Example 48

5-cvclopropyl-6-(/\/-((6-fluoro-1-hvdroxy-1 ,3-dihvdrobenzo[cl[1 ,2loxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: 4-fluoro-2-hydroxy-5-methylbenzoic acid

A solution of 4-fluoro-3-methylbenzoic acid (7 g, 45 mmol) (Alfa), Pd(OAc)₂ (1 g, 4.5 mmol), KOAc (8.8 g, 90 mmol) and benzoquinone (10.8 g, 45 mmol) in DMA (200 mL) was stirred under 10 MPa of 0₂ at 1 15 °C overnight. The reaction mixture was poured into ice/water (500 mL) and the aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to give 4-fluoro-2-hydroxy-5-methylbenzoic acid (2 g, 1 1.7 mmol, 25% yield) as a white solid. Step 2: methyl 4-fluoro-2-hydroxy-5-methylbenzoate

A solution of 4-fluoro-2-hydroxy-5-methylbenzoic acid (2 g, 1 1.7 mmol) and concentrated H₂S0₄ (0.15 mL) in MeOH (20 mL) was heated at 80 °C for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure.

The residue was poured into water/EA (100 mL/100 mL). The separated organic layer was dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford methyl 4-fluoro-2-hydroxy-5-methylbenzoate (.0.85 g,

4.6 mmol, 42%, yield) as a yellow oil.

Step 3: methyl 2-(tert-butyldimethylsilyloxy)-4-fluoro-5-methylbenzoate

A solution of methyl 4-fluoro-2-hydroxy-5-methylbenzoate (.1.5 g, 8.15 mmol), TBSCI

(1 .8 g, 12.2 mmol) and imidazole (1 .1 g, 16.3 mmol) in DMF (50 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into ice/water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column

chromatography to afford methyl 2-(tert-butyldimethylsilyloxy)-4-fluoro-5-methylbenzoate (2 g, 6.7 mmol, 80% yield) as a colorless oil. Step 4: methyl 5-(bromomethyl)-2-(tert-butyldimethylsilyloxy)-4-fluorobenzoate

To a solution of methyl 2-(tert-butyldimethylsilyloxy)-4-fluoro-5-methylbenzoate (2 g, 6.7 mmol) in CCI₄ (50 mL) were added NBS (1 .15 g, 6.5 mmol) and benzoyl peroxide (33.5 mg, 0.0335 mmol). The flask was purged with nitrogen several times and the reaction solution was heated at 80 °C for 12 h. The reaction mixture was poured into EA/water (100 mL/100 mL) and the separated organic layer was washed with water (3 x 50 mL) and dried over anhydrous Na₂S0₄ After the removal of solvent, the crude product was purified with column chromatography to afford methyl 5-(bromomethyl)-2-(tert-butyldimethylsilyloxy)-4- fluorobenzoate (2.1 g, 5.6 mmol, 75 %, yield) as a light yellow oil.

Step 5: methyl 2-(tert-butyldimethylsilyloxy)-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-4-fluorobenzoate

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (2 g, 4.9 mmol), methyl 5-(bromomethyl)-2- (tert-butyldimethylsilyloxy)-4-fluorobenzoate (1 .8 g, 4.9 mmol) and K₂C0₃ (1.35 g, 9.8 mmol) in MeCN (100 mL) was heated at 80 °C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 2-(tert-butyldimethylsilyloxy)-5-((N-(5-cyclopropyl-2-(4- fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-4- fluorobenzoate (0.95 g, 1.36 mmol, 30 % yield) as a white solid.

Step 6: methyl 5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-4-fluoro-2-hydroxybenzoate

A solution of 2-(tert-butyldimethylsilyloxy)-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-4-fluorobenzoate (0.95 g, 1 .36 mmol) and HCI (5N aq., 2 mL) in THF was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (200 mL), washed with brine (3 x 50 mL) and dried over anhydrous Na₂S0₄. Removal of the solvent under reduced pressure afforded 5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-4-fluoro-2-hydroxybenzoate (540 mg, 0.92 mmol, 67 % yield) as a white solid. Step 7: methyl 5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-4-fluoro-2-hydroxybenzoate To a solution of 5-((/V-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-4-fluoro-2-hydroxybenzoate (540 mg, 0.92 mmol) and DIEA (237 mg, 1 .84 mmol) in DCM (50 mL) was added Tf₂0 (387 mg, 1 .84 mmol) drop wise at 0 °C. After the addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice/water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column chromatography to give methyl 5-((/V-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-4-fluoro-2-hydroxybenzoate (450 mg, 0.64 mmol, 68 % yield) as a white solid.

Step 8: methyl 5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-4-fluoro-2-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2- yl)benzoate

A solution of 5-((/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-

6-yl)methylsulfonamido)methyl)-4-fluoro-2-hydroxybenzoate (450 mg, 0.64 mmol),

Pd(dppf)CI₂ (24 mg, 0.032 mmol), Pin₂B₂ (243 mg, 0.96 mmol) and KOAc (190 mg, 1.28 mmol) in dioxane (45 mL) was heated at 100 °C under nitrogen atmosphere overnight. The reaction mixture was poured into ice/water (200 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-4-fluoro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (250 mg, 0.36 mmol, 35 % yield) as a white solid.

Step 9: 5-cyclopropyl-6-(N-( ( 6-fluoro- 1-hydroxy-1 ,3-dihydrobenzo[c][ 1, 2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam

To a solution of 5-((/V-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-4-fluoro-2-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (250 mg, 0.36 mmol) in THF (25 mL) was added LiBH₄ (0.37 mL, 0.74 mmol, 2 M in THF) drop wise at 0 °C over 10 min and then stirred at 0 °C for 30 min. The reaction mixture was poured into ice/water (50 mL) and the aqueous layer was extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over Na₂S0₄. After the removal of solvent, the crude product was purified with reverse phase HPLC to afford 5-cyclopropyl-6-(N-((6-fluoro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-5-yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (79 mg, 0.14 mmol, 37 % yield) as a white solid. ¹H NMR (300MHz, CDCI3) δ: 7.85-7.80(m,2H), 7.31 -7.13(m„6H),5.78-5.76(m,1 H),5.19- 4.97(m,4H),3.08(s,3H),2.98-2.86(d,3H),2.20(m,1 H), 1 .05-0.90(m,3H),0.50(m, 1 H). LCMS(m/z, ES 567(M+H).

Example 49

5-cvclopropyl-2-(4-fluorophenyl)-6-(/V-(2-(1-hvdroxy-1 ,3-dihvdrobenzorciri2loxaborol-5- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide

Step 1: 2-bromo-5-iodobenzaldehyde

To a solution of 1-bromo-4-iodobenzene (10 g, 35.5 mmol, Alfa) in THF (60 mL), lithium 2,2,6,6-tetramethylpiperidide (5.2 g, 35.5 mmol) was added at -80°C under nitrogen atmosphere and the reaction mixture was stirred at -80 °C for 40 min. Then, DMF (20 mL) was added and the reaction solution was stirred at -90 °C for 20 min. The solution was warmed to rt, HCI (1 N, 20 mL) was added drop wise. The aqueous layer was extracted with EtOAc (180 mL). The combined organic layers were dried over anhydrous Na₂S0₄.

Evaporation of solvent under reduced pressure afforded 2-bromo-5-iodobenzaldehyde (12.4 g, 40 mmol, 1 13%).

Step 2: (2-bromo-5-iodophenyl)methanol

To a solution of 2-bromo-5-iodobenzaldehyde (12.4 g, 40 mmol) in MeOH (50 mL) was added NaBH₄ (3 g, 80 mmol) at 0 °C. After the addition, the reaction solution was stirred at rt for 30 minutes. The reaction solution was diluted with water (20 mL) and EtOAc (60 mL). The organic layer was separated and dried over anhydrous Na₂S0₄. After removal of solvent, the residue was purified with column chromatography to afford (2-bromo-5- iodophenyl)methanol (3.5 g, 1 1 .2 mmol, 28 % yield) as a white solid.

Step 3: (2-bromo-5-iodobenzyloxy)(tert-butyl)dimethylsilane

To a solution of (2-bromo-5-iodophenyl)methanol (3.5 g, 1 1 .2 mmol) and imidazole (1 .53g, 22.4 mmol) in DCM (85 mL) was added TBSCI (2.03 g, 13.4 mmol) at 0 °C. The solution was stirred at room temperature for 30 minutes and then diluted with water (20 mL) The organic layer was washed with brine (20 mL) and dried over anhydrous Na₂S0₄. After removal of solvent, the crude product was purified with flash column chromatography to afford (2-bromo-5-iodobenzyloxy)(tert-butyl)dimethylsilane (4.48 g, 10.5 mmol, 94 % yield) as a colorless oil. Step 4: (5-allyl-2-bromobenzyloxy)(tert-butyl)dimethylsilane

To a solution of (2-bromo-5-iodobenzyloxy)(ferf-butyl)dimethylsilane (10 g, 23.5 mmol) and tetrakis(triphenylphosphine)palladium (1.38 g, 1.2 mmol) in DMF(100 mL) was added allyltributyltin (9.37 g, 28.2 mmol) at rt. The reaction solution was stirred at rt for 48 hours and then diluted with water (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with flash column chromatography to afford (5-allyl-2-bromobenzyloxy)(tert- butyl)dimethylsilane (7 g, 20.5 mmol, 87 % yield) as a colorless oil.

Step 5: 2-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)ethanol

A solution of methyl (5-allyl-2-bromobenzyloxy)(ferf-butyl)dimethylsilane (7 g, 20.5 mmol) in CH₂CI₂/MeOH (30 ml / 30 ml) was saturated with a stream of 0₃ at -78°C. The mixture was stirred for 30 min until the reaction mixture turned blue. The solution was purged with N₂ for 30 minutes and then NaBH₄ (1 .2 g, 30.9 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hours. After the addition of water (50 mL), the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with reverse phase HPLC to afford 2-(4-bromo-3- ((tert-butyldimethylsilyloxy)methyl)phenyl)ethanol (400 mg, 1.16 mmol, 5.6%) as a colorless oil. ¹ H NMR (300MHz, CDCI3) δ: 7.44 - 7.46(m,2H), 7.00 - 7.04 (m, 1 H), 4.75(s,2H), 3.87 - 3.91 (t, 2H), 2.86 - 2.90 (t, 2H), 0.99 (s,1 H),

Step 6: (2-bromo-5-(2-bromoethyl)benzyloxy)(tert-butyl)dimethylsilane

A solution of 2-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)ethanol (410 mg, 1.12 mmol), PPh₃ (632 mg, 2.24 mmol) and NBS (418 mg, 2.24 mmol) in dichloromethane (20mL) was stirred at rt for 10 minutes under nitrogen atmosphere. The reaction solution was poured into NaHC0₃ (saturated aq, 20 mL), extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford (2-bromo-5-(2-bromoethyl)benzyloxy)(tert- butyl)dimethylsilane (373 mg, 0.92 mmol, 77 % yield). Step 7: 6-(N-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenethyl)methyl sulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6-(methylsulfonamido) benzofuran-3-carboxamide (330 mg, 0.83 mmol), (2-bromo-5-(2-bromoethyl) benzyloxy)(tert- butyl)dimethylsilane (373 mg, 0.92 mmol), Kl (7 mg, 0.04 mmol) and K₂C0₃ (372 mg, 2.7 mmol) in dry DMF (15 mL) was heated at 80 °C for 2 hours under a nitrogen atmoshpere. The reaction solution was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and then dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-3-((ferf- butyldimethylsilyloxy)methyl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)- A/-methylbenzofuran-3-carboxamide (344 mg, 0.47 mmol, 57 % yield) as a brown solid.

Step 8: 6-(N-(3-((tert-butyldimethylsilyloxy)methyl)-4-(4, 4, 5, 5-tetramethyl-1 ,3, 2- dioxaborolan- 2-yl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-m

carboxamide

A solution of 6-(/V-(4-bromo-3-((ferf- butyldimethylsilyloxy)methyl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)- A/-methylbenzofuran-3-carboxamide (344 mg, 0.47 mmol), bis(pinacolato)diboron (238 mg, 0.94 mmol), potassium acetate (138 mg, 1.41 mmol) and PdCI₂(dppf)-CH₂CI₂ (57 mg, 0.05 mmol) in dioxane (15 mL) was heated at reflux overnight under a nitrogen atmosphere. After cooling down to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(/V-(3-((fert- butyldimethylsilyloxy)methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methylbenzofuran-3-carboxamide (355 mg, 0.46 mmol, 97 % yield) as a white solid.

Step 9: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(1 -hydroxy- 1, 3- dihydrobenzo[c][1,2]oxaborol-5-yl)ethyl)methylsulfonamido)-N-methylbenzofuran

carboxamide

A solution of 6-(/V-(3-((fert-butyldimethylsilyloxy)methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methylbenzofuran-3-carboxamide (355 mg, 0.46 mmol) and pyridinium 4- methylbenzenesulfonate (230 mg, 0.92 mmol) in EtOH (15 mL) was heated at 30 °C overnight at. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with H₂0 (20 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with pre-HPLC to afford 5- cyclopropyl- 2-(4-fluorophenyl)-6-(/V-(2-(1-hydroxy-1 ,3-dihydrobenzo[c][i,2]oxaborol-5- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide (160 mg, 0.28 mmol, 62 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.84 (m, 2H), 7.45 (d, 2H), 7.18 (m, 5H), 4.88 (s,2H), 3.95( m, 2H), 2.95 (s, 3H), 2.85 (s, 3H), 2.82 (m, 2H), 2.26 (m, 1 H), 0.99 (m, 1 H),0.83 (m, 2H), 0.39 (m, 1 H). LCMS (m/z, ES⁺)= 563.0 (M+H)

Example 50

Methyl 5-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-1-hvdroxy-1 ,3-dihydro-2, 1 -benzoxaborole-7-carboxylate

Step 1: 2,6-dibromo-p-toluidine

Cooled dioxane (12.78ml_) was treated with bromine (7.72 mL, 0.150 mol) via syringe to obtain a orange yellow complex. Then a solution of p-toluidine (16.07 g, 0.15 mol) in dioxane (120 mL) was cooled to 8°C in ice-water bath and treated with the complex prepared above portion wise. Throughout the addition the internal temperature was maintained below 14°C. After addition, the solution was stirred for another 10 minutes, then filtered to collect the solids. The filter cake was washed with 50mL water, diluted NaOH, and then 10mL water to get a batch of off-white solid. The filtrate was neutralized with more diluted NaOH, concentrated and filtered to get another batch of solid. The combined solids were

recrystallized from hot ethanol to give 2,6-dibromo-p-toluidine (15.34g, 0.058 mol, 38.6 % yield) as an off-white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ: 7.21 (s, 2 H), 3.71 - 4.70 (br, 2 H), 2.17 - 2.26 (s, 3 H). Step 2: dimethyl 2-amino-5-methyl-1,3-benzenedicarboxylate

A solution of 2,6-dibromo-p-toluidine (5g, 18.87 mmol), TEA (2.101 g, 20.76 mmol), palladium acetate (0.847 g, 3.77 mmol) and dppf (3.14 g, 5.66 mmol) in DMSO (30 mL) and methanol (20 mL) was maintained at 80°C for 19 hours under a CO atmosphere (-70 PSI). The solution was filtered through celite, diluted with EtOAc (100mL), and the organic layer was washed with water and then with brine. The organic layer was collected, dried over sodium sulfate, filtered, concentrated and purified by silica column chromatography to give dimethyl 2-amino-5-methyl-1 ,3-benzenedicarboxylate (1 .85 g, 8.29 mmol, 43.9 % yield) as a yellow solid . ¹H NMR (400 MHz, CHLOROFORM-d) δ: 8.13 (br. s., 1 H), 7.93 (s, 2 H), 7.61 (br. s., 1 H), 3.89 (s, 6 H), 2.24 (s, 3 H).

Step 3: dimethyl 2-bromo-5-methyl-1,3-benzenedicarboxylate

A solution of dimethyl 2-amino-5-methyl-1 ,3-benzenedicarboxylate (1 .5g, 6.72 mmol) in acetonitrile (20 mL) was cooled to 0°C, then 48% aqueous hydrobromide (7.60 mL, 67.2 mmol) was added drop wise via dropping funnel over 10 minutes, then sodium nitrite (0.510 g, 7.39 mmol) in 2mL water was added drop wise over 30 minutes. After addition, the mixture was stirred under 0°C for another 10 minutes and then copper bromide (1.131 g, 7.73 mmol) was added portion wise over 30min. The solution was stirred at room temperature overnight and then at 70°C for 1 hour. The solution was diluted with water and extracted with EtOAc. The organic layer dried over sodium sulfate, filtered, concentrated and purified by column chromatography to give dimethyl 2-bromo-5-methyl-1 ,3-benzenedicarboxylate (1 .55g, 5.40 mmol, 80 % yield) as a white foam. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.56 (s, 2 H), 3.92 (s, 6 H), 2.36 (s, 3 H).

Step 4: dimethyl 2-bromo-5-(bromomethyl)-1,3-benzenedicarboxylate

A solution of dimethyl 2-bromo-5-methyl-1 ,3-benzenedicarboxylate (1 .5g, 5.22 mmol),

NBS (1 .023 g, 5.75 mmol) and AIBN (0.043 g, 0.261 mmol) in CCI₄ (20 mL) was refluxed for 5.5 hours. The solids were removed via vacuum filtration and the filtrate was concentrated and the resulting residue was purified by column chromatography to give dimethyl 2-bromo- 5-(bromomethyl)-1 ,3-benzenedicarboxylate (0.63g, 1.721 mmol, 32.9% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.75 (s, 2 H), 4.44 (s, 2 H), 3.97 (s, 6 H).

Step 5: dimethyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}-1,3-benzenedicarboxylate

A mixture of dimethyl 2-bromo-5-(bromomethyl)-1 ,3-benzenedicarboxylate (0.6 g, 1.639 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (0.51 g, 1 .267 mmol), potassium carbonate (0.175 g, 1.267 mmol) and potassium iodide (0.021 g, 0.127 mmol) in DMF (6 mL) was warmed to 30°C for 3 hours under N₂ atmosphere. The solids were removed via filtration and the filtrated was diluted with water, extracted with EtOAc, and the organic layer was dried over Na₂S0₄, filtered, concentrated and purified by column chromatography to give dimethyl 2-bromo-5- {[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}-1 ,3-benzenedicarboxylate (0.85g, 1 .236 mmol, 98% yield) as a sticky pale yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ : 7.87 (dd, J=8.0, 5.7 Hz, 2 H), 7.59 (s, 2 H), 7.27 (s, 2 H), 7.14 - 7.23 (m, 2 H), 5.78 (br. s., 1 H), 4.87 (q, 2 H), 3.93 (s, 6 H),3.06 (s, 3 H), 3.00 (d, J=4.7 Hz, 3 H), 2.09 - 2.22 (m, 1 H) , 1.00 - 1.14 (m, 1 H), 0.83 - 0.97 (m, 2 H), 0.52 (d, J=5.1 Hz, 1 H).

Step 6: dimethyl 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl} (methylsulfonyl)amino]methyl}-2-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2- yl)- 1, 3-benzenedicarboxylate

A solution of dimethyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}-1 ,3- benzenedicarboxylate (0.85g, 1.236 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane (0.628 g, 2.473 mmol), Pd(dppf)CI₂-CH₂CI₂ (0.101 g, 0.124 mmol) and potassium acetate (0.364 g, 3.71 mmol) in 1 ,4-dioxane (20 mL) was refluxed overnight under N₂ atmosphere. The solution was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by column

chromatography to give dimethyl 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl) amino]methyl}-2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 , 3-benzenedicarboxylate (0.26g, 0.354mmol, 28.64% yield) as a sticky white solid. LC-MS (m/z, ES⁺)=735 (M+H).

Step 7: methyl 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]methyl}-1 -hydroxy-1 ,3-dihydro-2, 1 -benzoxaborole-7-carboxylate

A solution of dimethyl 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]- 1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 , 3-benzenedicarboxylate (0.26g, 0.354 mmol) in anhydrous THF (20 mL) was treated with 4.15mL of LiBH₄ (0.202 mL, 8.31 mmol, 2.0M THF solution), and stirred at room temperature until the starting material was completely consumed. The mixture was poured into ice water and extracted with EtOAc. The organic layer dried over sodium sulfate, filtered, concentrated and purified by column chromatography to give methyl 5-{[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-1 -hydroxy-1 , 3-dihydro-2, 1 -benzoxaborole-7-carboxylate (28.5 mg, 0.047 mmol, 13.25% yield) as a off-white solid. ¹ H NMR (400 MHz,

CHLOROFORM-d) δ: 8.41 (s, 1 H), 7.95 (s, 1 H), 7.79 - 7.86 (m, 2 H), 7.47 (s, 1 H), 7.24 (s, 1 H), 7.19 (t, 2 H), 5.75 (d, 1 H), 5.05 - 5.15 (m, 3 H), 4.87 (d, 1 H), 3.95 (s, 3 H), 3.07 (s, 3 H), 2.99 (d, 3 H), 2.14 - 2.24 (m, 1 H), 2.02 (s, 1 H), 1 .00 - 1 .12 (m, 1 H), 0.85 - 0.98 (m, 2 H), 0.49 - 0.60 (m, 1 H). LC-MS(m/z, ES⁺)= 607 (M+H). Example 51

5-cvclopropyl-2-(4-fluorophenyl)-6-[{[1 -hvdroxy-7-(hvd^

benzoxaborol-5-yllmethyl}(methylsulfonyl)aminol-N-methyl-1-benzofuran-3-carboxamide

5- cyclopropyl-2-(4-fluorophenyl)-6-[{[1-hydroxy-7-(hydroxymethyl)-1 ,3-dihydro-2, 1- benzoxaborol-5-yl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofum

To a solution of methyl 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}-1 -hydroxy-1 ,3- dihydro-2, 1-benzoxaborole-7-carboxylate (35mg, 0.058mmol) in anhydrous THF (5 mL) was added 1 .4ml_ of LiBH₄ (62.9 mg, 2.89 mmol, 2.0M THF solution) and stirred under room temperature until the starting material was completely consumed. The solution was washed with water, extracted with EtOAc and the organic layer was dried over Na₂S0₄, filtered, concentrated and purified by reverse phase HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-

6- [{[1 -hydroxy-7-(hydroxymethyl)-1 ,3-dihydro-2, 1-benzoxaborol-5- yl]methyl}(methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide (14.5 mg, 0.025 mmol, 43.4 % yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d₆) δ: 8.89 (br. s., 1 H), 8.35 - 8.50 (m, 1 H), 8.14 - 8.20 (m, 1 H), 7.80 - 8.01 (m, 3 H), 7.39 (t, 2 H), 7.29 (s, 1 H), 7.18 (s, 1 H), 6.89 (s, 1 H), 5.43 (br. s., 1 H), 5.00 (d, 1 H), 4.91 (s, 2 H), 4.84 (d, 1 H), 4.66 (s, 2 H),3.21 (br. s., 4 H), 2.79 (d, J=3.5 Hz, 3 H), 2.27 - 2.38 (m, 1 H), 0.86 - 1 .00 (m, 1 H), 0.68 - 0.86 (m, 2 H), 0.12 - 0.26 (m, 1 H). LC-MS (m/z, ES⁺)= 579 (M+H).

Example 52

6-(/\/-((7-chloro-1 -hydroxy-1.S-dihydrobenzorcir^'/^loxaborol-S-vDmethvDmethylsulfonamido)- 5-cvclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide

Step 1: 2-bromo-6-chloro-4-methylbenzenamine To a solution of 2-chloro-4-methylbenzenamine (5.0 g, 35.3 mmol) in acetic acid (40 mL) was added NBS (6.9 g, 38.3 mmol) in portions at 15 °C under nitrogen atmosphere_. After the addition, the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were washed with water (2 x 150 mL) and Na₂C0₃ (10% aq. 150 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 2-bromo-6-chloro-4- methylbenzenamine (3.5 g, 15.9 mmol, 45 % yield). Step 2: methyl 2-amino-3-chloro-5-methylbenzoate

A solution of 2-bromo-6-chloro-4- methylbenzenamine (3.5 g, 16 mmol), Pd(OAc)₂ (0.72 g, 3.2 mmol), dppf (2.69 g, 4.8 mmol) and EtN₃ (1.62 g, 16 mmol) in DMSO (105 mL) and MeOH (69 mL) was heated at 80 °C for 16 hours under 2.2 MPa of carbon monoxide. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (300 mL), washed with water (3x200 mL) and brine (200 mL), and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford methyl 2-amino-3- chloro-5-methylbenzoate (3.15 g, 15.8 mmol, 98 % yield) as a white solid. Step 3: methyl 2-bromo-3-chloro-5-methylbenzoate

To a solution of methyl 2-amino-3- chloro-5-methylbenzoate (3.15 g, 15.8 mmol) in MeCN (20mL) was added HBr (47% aq. 19.5 mL) drop wise at 0 °C over 10 minutes. NaN0₂ (1 .12 g, 17.4 mmol) in water (5 mL) was added drop wise over 1 hour at 0 °C. After the addition, the solution was stirred for 5 minutes at 0 °C followed by the addition of CuBr (2.64 g, 18.2 mmol) in portions over 30 minutes. The reaction mixture was heated at 70 °C for 1 hour. After cooling to 0 °C, water (30 mL) was added and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with cold water (70 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column

chromatography to afford methyl 2-bromo-3-chloro-5-methylbenzoate (3.1 g, 1 1 .8 mmol, 74 % yield) as a light yellow liquid.

Step 4: methyl 2-bromo-5-(bromomethyl)-3-chlorobenzoate

A solution of methyl 2-bromo-3-chloro-5-methylbenzoate (3.1 g, 1 1 .8 mmol), benzoyl peroxide (145 mg, 0.6 mmol) and /V-bromosuccinimide (2.31 g, 13.0 mmol) in CCI₄ (50mL) was heated under reflux for 48 hours. After the reaction solution was cooled down to room temperature, it was concentrated under reduced pressure and the residue was purified with column chromatography to afford methyl 2-bromo- 5-(bromomethyl)-3-chlorobenzoate (1.54 g, 4.5 mmol, 38 % yield) as a white solid.

Step 5: methyl 2-bromo-3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)benzoate

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (600 mg, 1.5 mmol), methyl 2-bromo-5- (bromomethyl)-3- chlorobenzoate (769 mg, 2.25 mmol), Kl (12 mg, 0.07 mmol) and K₂C0₃ (621 mg, 4.5 mmol) in dry DMF (25 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction solution was diluted with water (75 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column chromatography to afford methyl 2-bromo-3-chloro-5-((/V-(5- cyclopropyl-2-(4- fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)benzoate (700 mg, 1.05 mmol, 71 % yield) as a white solid.

Step 6: methyl 3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4, 4, 5, 5-tetramethyl-1 , 3, 2- dioxaborolan-2-yl)benzoate

A solution of methyl 2-bromo-3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)benzoate (700 mg, 1.05 mmol), bis(pinacolato)diboron (533 mg, 2.1 mmol), potassium acetate (308 mg, 3.15 mmol) and PdCl2(dppf)-CH₂Cl2 (1 15 mg, 0.1 mmol) in dioxane (25 mL) was degassed and refilled with nitrogen three times and then heated at 100 °C overnight. After the reaction solution was cooled to room temperature, it was poured into water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford methyl 3-chloro-5-((/V-(5- cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (1 15 mg, 0.16 mmol, 15 % yield) as a white solid.

Step 7: 6-(N-( (7-chloro- 1 -hydroxy- 1, 3-dihydrobenzo[c][ 1, 2]oxaborol-5- yl)methyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide

To a solution of methyl 3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (1 15mg, 0.16 mmol ) in THF (15 mL) was added LiBH₄ (2M in THF, 0.24 ml, 0.48 mmol) dropwise at -5 °C. After the addition, the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (15 ml_), extracted with EtOAc (3 x 20 ml_). The combined organic layers were washed with brine (30 ml.) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by reverse phase HPLC to afford 6-(/V-((7-chloro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-5-yl)methyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-/V-methylbenzofuran-3-carboxamide (75 mg, 0.12 mmol, 18 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.94-7.89 (m, 2H), 7.65 (S, 1 H), 7.29-7.19 (m, 4H), 7.03 (s, 1 H), 5.06-4.86 (m, 4H), 3.32 (s, 3H), 2.93 (S, 3H), 2.28-2.26 (m, 1 H), 1 .03-0.81 (m, 3H), 0.34-0.32 (m, 1 H). LCMS (m/z, ES⁺) = 583.1 (M+H)

Example 53

5-Cvclopropyl-2-(4-fluorophenyl)-6-rr(1-hvdroxy-3,4-dihvdro-1 /-/-2, 1-benzoxaborin-6- yl)methyll(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

Step 1: Methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamin

benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (5.00 g, 12.4 mmol), methyl 2-bromo-5-(bromomethyl)benzoate (7.65 g, 24.85 mmol, 60% pure by LCMS) and potassium carbonate (3.43 g, 24.85 mmol) in acetonitrile (100 mL) was heated to 50° for 4 hours. To this was added additional methyl 2- bromo-5-(bromomethyl)benzoate (1 .00 g, 3.25 mmol, 60% pure by LCMS) and heating was continued for another 3 hours. The mixture was cooled to room temperature, filtered and concentrated to remove most of the acetonitrile. The residue was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded methyl 2-bromo-5-{[{5-cyclopropyl-2-(4- fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}benzoate (6.59 g, 84%) as a light yellow foam. ¹ H NMR (CHLOROFORM-d) : 7.86 (dd, J = 8.7, 5.3 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1 H), 7.57 (d, J =

8.2 Hz, 1 H), 7.15 - 7.26 (m, 5H), 5.76 (m, 1 H), 4.92 - 5.00 (m, 1 H), 4.72 - 4.79 (m, 1 H), 3.89 (s, 3H), 3.04 (s, 3H), 2.99 (d, J = 4.9 Hz, 3H), 2.1 1 - 2.21 (m, 1 H), 1 .01 - 1 .10 (m, 1 H), 0.87 - 0.98 (m, 2H), 0.54 (q, 1 H). LCMS {m/z, ES⁺) = 629 (M+H).

Step 2: 6-[{[4-Bromo-3-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl- 2-(4-fluorophenyl)-N-methyl- 1-benzofuran-3-carboxamide

A solution of methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate (4.66 g, 7.40 mmol) in THF (100 ml.) and methanol (10 ml.) was treated with a solution of lithium borohydride (18.5 ml_, 2.0 M in THF). After stirring for 16 hours, the reaction was quenched with 1 N sodium hydroxide (25 ml.) and stirred for 30 min. The reaction mixture was concentrated to remove most of the THF. The residue was diluted with water and extracted with ethyl acetate (4x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford 6-[{[4-bromo-3-

(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (2.84 g, 64%) as a tan solid. ¹H NMR (CHLOROFORM- cQ δ: 7.86 (dd, J = 8.7, 5.3 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1 H), 7.37 (d, J = 1 .7 Hz, 1 H), 7.26 (br. s., 2H), 7.19 (t, J = 8.6 Hz, 2H), 7.07 (dd, J = 8.2, 2.0 Hz, 1 H), 5.75 (d, J = 4.5 Hz, 1 H), 4.89 - 5.05 (m, 1 H), 4.61 - 4.81 (m, 3H), 2.91 - 3.09 (m, 6H), 2.12 - 2.26 (m, 1 H), 0.80 - 1 .13 (m, 3H), 0.44 - 0.63 (m, 1 H). LCMS {m/z, ES⁺) = 601 (M+H).

Step 3: 6-[[(4-Bromo-3-formylphenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[{[4-bromo-3-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (0.61 g, 1 .01 mmol) in dichloromethane (100 ml.) was treated with manganese dioxide (0.88 g, 10.1 mmol) and allowed to stir at room temperature overnight. The reaction mixture was filtered through a pad of celite, rinsing well with dichloromethane and ethyl acetate. The filtrate was

concentrated and the residue purified by silica gel chromatography (0 to 75% ethyl acetate in hexanes) to afford 6-[[(4-bromo-3-formylphenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl- 2-(4-fluorophenyl)-/V-methyl-1 -benzofuran-3-carboxamide (0.48 g, 79%) as a colorless oil. ¹H NMR (CHLOROFORM-d) δ: 10.29 (s, 1 H), 7.85 (dd, J = 8.7, 5.3 Hz, 2H), 7.68 (d, J = 2.2 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.44 - 7.57 (m, 1 H), 7.25 (s, 1 H), 7.19 (t, J = 8.6 Hz, 2H), 5.64 - 5.85 (m, 1 H), 4.89 - 5.05 (m, 1 H), 4.72 - 4.89 (m, 1 H), 2.89 - 3.13 (m, 6H), 2.09 - 2.25 (m, 1 H), 0.99 - 1 .15 (m, 1 H), 0.80 - 0.99 (m, 2H), 0.40 - 0.62 (m, 1 H). LCMS {m/z, ES⁺) = 599 (M+H). Step 4: 6-[{[4-Bromo-3-(2-oxoethyl)phenyl]methyl}(methylsulfonyl)am

fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[[(4-bromo-3-formylphenyl)methyl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (0.71 g, 1 .18 mmol) in DMF (15 mL) was treated with (methoxymethyl)triphenylphosphonium chloride (0.49 g, 1.42 mmol) and potassium f-butoxide (0.16 g, 1.42 mmol). The reaction was stirred at room temperature overnight, then additional (methoxymethyl)triphenylphosphonium chloride (0.16 g, 0.47 mmol) and potassium f-butoxide (0.053 g, 0.47 mmol) were added and the reaction was stirred another 6 hours. The reaction was quenched with 5N HCI, diluted with water and extracted with ethyl acetate. The organic layer was washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated. The residue was taken up in THF (15 mL), treated with 5N HCI (15 mL) and heated under reflux overnight. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[{[4-bromo-3-(2- oxoethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1- benzofuran-3-carboxamide (0.42 g, 58%) as a pale yellow oil. ¹ H NMR (CHLOROFORM-d) δ: 9.66 (t, J = 1 .5 Hz, 1 H), 7.81 - 7.95 (m, 2H), 7.47 - 7.57 (m, 1 H), 7.24 (d, J = 2.5 Hz, 2H), 7.16 - 7.23 (m, 2H), 7.09 (dd, J = 8.2, 2.2 Hz, 1 H), 7.03 (d, J = 2.1 Hz, 1 H), 5.87 (d, J = 4.5 Hz, 1 H), 4.93 (d, J = 14.4 Hz, 1 H), 4.71 (d, J = 14.3 Hz, 1 H), 3.81 (dd, J = 3.1 , 1.5 Hz, 2H), 3.03 (s, 3H), 2.96 - 3.02 (m, 3H), 2.08 - 2.20 (m, 1 H), 0.98 - 1.12 (m, 1 H), 0.83 - 0.97 (m, 2H), 0.48 - 0.62 (m, 1 H). LCMS {m/z, ES⁺) = 613 (M+H).

Step 5: 6-[{[4-Bromo-3-(2- {[(methyloxy)methyl]oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino

fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[{[4-bromo-3-(2-oxoethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (0.42 g, 0.69 mmol) in methanol (10 mL) was cooled to 0° and treated with sodium borohydride (26 mg, 0.69 mmol). The reaction was allowed to warm to room temperature. After 1 hour, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in dichloromethane (10 mL) and cooled to 0°. The solution was treated with DIEA (0.14 mL, 0.82 mmol) and chloromethyl methyl ether (62 uL, 0.82 mmol). The reaction mixture was allowed to warm to rt overnight. The reaction was poured into water and extracted with dichloromethane (2x). The combined organic layers were washed with water (1 x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[{[4-bromo-3-(2-

{[(methyloxy)methyl]oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclop

fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (0.38 g, 84%) as a colorless oil. LCMS {m/z, ES⁺) = 659 (M+H).

Step 6: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[( 1-hydroxy-3,4-dihydro-1 H-2, 1 -benzoxaborin-6- yl)methyl](methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

A mixture of 6-[{[4-bromo-3-(2- {[(methyloxy)methyl]oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (0.38 g, 0.58 mmol), potassium acetate (1 13 mg, 1.15 mmol), bis(pinacolato)diboron (190 mg, 0.75 mmol), sodium bromide (59 mg, 0.58 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (43 mg, 0.058 mmol) in 1 ,4-dioxane (10 ml.) in a thick-walled glass pressure vessel was degassed, then heated at 95°C with stirring for 20 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. The residue was dissolved in 1 ,4-dioxane (40 ml.) and treated with 5N HCI (20 ml.) and stirred at room temperature for 4 h. The reaction mixture was diluted with water, concentrated to remove most of the organics, then extracted with ethyl acetate. The organic layer was washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane), then a second purification by reverse phase HPLC afforded 5-cyclopropyl-2-(4-fluorophenyl)- 6-[[(1 -hydroxy-3,4-dihydro-1 /-/-2, 1-benzoxaborin-6-yl)methyl](methylsulfonyl)amino]-/\/- methyl-1 -benzofuran-3-carboxamide (188 mg, 58%) as a white foam. ¹H NMR (METHANOL- d4) δ: 7.85 - 7.96 (m, 2H), 7.58 (s, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.13 (m, 2H), 7.02 (s, 1 H), 4.92 - 4.98 (m, 1 H), 4.77 - 4.84 (m, 1 H), 4.15 (t, J = 6.0 Hz, 2H), 3.15 (s, 3H), 2.92 (s, 3H), 2.83 (t, J = 5.9 Hz, 2H), 2.16 - 2.34 (m, 1 H), 0.90 - 1.05 (m, 1 H), 0.68 - 0.86 (m, 2H), 0.25 - 0.41 (m, 1 H). LCMS {m/z, ES⁺) = 563 (M+H).

Example 54

5-Cvclopropyl-/\/-ethyl-6-rr(7-fluoro-1-hvdroxy-1 ,3-dihvdro-2, 1-benzoxaborol-5- l)methyll(methylsulfonyl)aminol-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide

Step 1: 5-Cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)ami 1-benzofuran-3- carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1 -benzofuran- 3-carboxylic acid (5 g, 12.84 mmol) in DMF (30 mL) was cooled in an ice bath. To this solution was added DIEA (8.97 mL, 51.4 mmol) and ethylamine hydrochloride (1.571 g, 19.26 mmol). After stirring for 10 min, 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (1 1 .47 mL, 19.26 mmol) was added over 2 minutes and the reaction was stirred for 40 minutes before the ice bath was removed. The reaction did not progress and was poured into water and stirred for 20 min. The suspension was filtered and dried under vacuum to afford 5-cyclopropyl-/V-ethyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (4.14 g, 9.94 mmol, 77 % yield) as a tan solid. ¹H NMR (DMSO- d₆) δ: 9.31 (br. s., 1 H), 8.52 (t, J = 5.57 Hz, 1 H), 7.95 (dd, J = 5.37, 8.70 Hz, 2H), 7.60 (s, 1 H), 7.38 (t, J = 8.89 Hz, 2H), 7.14 (s, 1 H), 3.27 - 3.40 (m, 2H), 3.05 (s, 3H), 2.25 - 2.38 (m, 1 H), 1 .14 (t, J = 7.13 Hz, 3H), 0.95 - 1 .04 (m, 2H), 0.63 - 0.74 (m, 2H). LCMS {m/z, ES⁺) = 417.

Step 2: Methyl 2-bromo-5-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1- benzofuran-6-yl](methylsulfonyl)amino]methyl}-3-fluorobenzoate

A mixture of 5-cyclopropyl-/V-ethyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (0.50 g, 1.20 mmol), methyl 2-bromo-5-(bromomethyl)-3- fluorobenzoate (0.47 g, 1.44 mmol) and potassium carbonate (0.33 g, 2.40 mmol) in acetonitrile (20 mL) was heated to 50° for 1 .5 h. The mixture was cooled to room

temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (1x) and brine (1 x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded methyl 2-bromo-5-{[[5-cyclopropyl-3- [(ethylamino)carbonyl]-2-(4-fluorophenyl)-1 -benzofuran-6-yl](methylsulfonyl)amino]methyl}-3- fluorobenzoate (0.72 g, 91 %) as a pale yellow foam. ¹H NMR (Acetone) δ: 8.00 - 8.08 (m, 2H), 7.73 (s, 1 H), 7.56 - 7.64 (m, 2H), 7.44 (dd, J = 9.2, 1 .8 Hz, 1 H), 7.29 (t, J = 8.8 Hz, 2H), 7.09 (s, 1 H), 5.06 - 5.13 (m, 1 H), 4.90 - 4.98 (m, 1 H), 3.85 (s, 3H), 3.45 (quin, J = 6.7 Hz,

2H), 3.23 (s, 3H), 2.29 - 2.39 (m, 1 H), 1 .20 (t, J = 7.2 Hz, 3H), 0.93 - 1.02 (m, 1 H), 0.74 - 0.89 (m, 2H), 0.23 - 0.32 (m, 1 H). LCMS {m/z, ES⁺) = 661 (M+H).

Step 3: 5-Cyclopropyl-N-ethyl-6-[[(7-fluoro-1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-2-(4-fluorophenyl)-1-benzofura

A mixture of methyl 2-bromo-5-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4- fluorophenyl)-1 -benzofuran-6-yl](methylsulfonyl)amino]methyl}-3-fluorobenzoate (0.72 g, 1.09 mmol), potassium acetate (0.21 g, 2.18 mmol), bis(pinacolato)diboron (0.36 g, 1.42 mmol), sodium bromide (1 12 mg, 1 .09 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (80 mg, 0.1 1 mmol) in 1 ,4-dioxane (10 mL) in a thick-walled glass pressure vessel was degassed, then heated at 95°C with stirring for 22 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded methyl 5-{[[5-cyclopropyl-3- [(ethylamino)carbonyl]-2-(4-fluorophenyl)-1 -benzofuran-6-yl](methylsulfonyl)amino]methyl}-3- fluoro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (0.75 g, 67% pure by LC/MS) as a colorless oil. This material was dissolved in THF (15 mL), cooled in an ice bath, treated with lithium borohydride (1 .6 mL, 2.0 M in THF) and stirred for 1 h. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization afforded 5-cyclopropyl-/V-ethyl-6-[[(7-fluoro-1- hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-5-yl)methyl](methylsulfonyl)amino]-2-(4-fluorophenyl)- 1-benzofuran-3-carboxamide (297 mg, 39% over 2 steps) as a white solid. ¹H NMR (DMSO- d₆) δ: 9.24 (s, 1 H), 8.51 (t, J = 5.6 Hz, 1 H), 7.93 (dd, J = 8.7, 5.4 Hz, 2H), 7.87 (s, 1 H), 7.38 (t, J = 8.8 Hz, 2H), 7.19 (s, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 6.91 (s, 1 H), 5.02 (d, J = 14.6 Hz, 1 H), 4.93 (s, 2H), 4.85 (d, J = 14.7 Hz, 1 H), 3.27 - 3.38 (m, 2H), 3.18 - 3.27 (m, 3H), 2.22 - 2.36 (m, 1 H), 1 .1 1 (t, J = 7.2 Hz, 3H), 0.87 - 1.02 (m, 1 H), 0.67 - 0.84 (m, 2H), 0.12 - 0.26 (m, 1 H). LCMS {m/z, ES⁺) = 581 (M+H).

Example 55

5-cvclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1-hvdroxy-1 ,3-dihvdrobenzorcin ,2loxaborol-3- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide

Step 1: 1-(2-bromop enyl)prop-2-en-1-ol

To a solution of 2-bromobenzaldehyde (10.0 g, 54 mmol, Alfa Aesar) in THF (90 mL) was added vinyl-MgBr (33.8 mL, 1.6 mol in THF) drop wise at 0 °C for 1 .5h under N₂ atmosphere. The reaction mixture was slowly warmed to room temperature and kept stirring for 1 hour. The reaction mixture was diluted with NH₄CI (90 mL) and extracted with Et₂0 (3 x 100 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL) and then dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with column chromatography to afford 1 -(2-bromophenyl)prop-2-en- 1 -ol (9.16 g, 43 mmol, 79% yield) as a colorless liquid. Step 2: (1-(2-bromophenyl)allyloxy)(tert-butyl)dimethylsilane

To a solution of 1-(2-bromophenyl)prop-2-en-1-ol (9.16 g, 43 mmol) in DMF (60ml_) were added ferf-butylchlorodimethylsilane (7.77 g, 51 .6 mmol) and imidazole (5.85 g, 86 mmol) at room temperature. The mixture was stirred for 3 hours at room temperature and then diluted with water (100ml_) and extracted with EtOAc (3 x 100ml_). The combined organic layers were washed with water (150 mL) and brine (150 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford (1-(2- bromophenyl)allyloxy)(tert-butyl)dimethylsilane (13.85 g, 42 mmol, 98 % yield) as a white solid. Step 3: 3-(2-bromophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol

To a solution of (1 -(2-bromophenyl)allyloxy)(tert-butyl)dimethylsilane (12.8 g, 39 mmol) in THF (250mL) was added 9-BBN (5.7 g, 23.4 mmol) at room temperature and the reaction solution was stirred at room temperature overnight. The reaction mixture was quenched with NaOH (1 M aq, 180 mL). After stirring for 15 mins, H₂0₂ (30%, 450 mL) was added drop wise to the reaction solution. After the addition, the reaction solution was stirred at room temperature for 30 minutes and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 3-(2-bromophenyl)-3-(tert- butyldimethylsilyloxy)propan-1 -ol (1 1.9 g, 34.5 mmol, 85 % yield) as a yellow oil.

Step 4: (3-bromo-1-(2-bromophenyl)propoxy)(tert-butyl)dimethylsilane

To a solution of 3-(2-bromophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol (5.0 g, 14.5 mmol) and NBS ( 5.16 g, 29 mmol) in DCM (50 mL) was added PPh₃ (7.60 g, 19.2 mmol) in DCM (15 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at rt for 5 mins and then poured into ice water (50 mL), extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column

chromatography to afford (3-bromo-1-(2-bromophenyl)propoxy)(tert-butyl)dimethylsilane (3.5 g, 8.6 mmol, 59 % yield) as a colorless liquid. Step 5: 6-(N-( 3-( 2-bromophenyl)-3-(tert-butyldimethylsilyloxy)propyl)me

cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (2.5g, 6.2 mmol), (3-bromo-1-(2- bromophenyl)propoxy)(tert-butyl)dimethylsilane (3.5 g, 8.6 mmol), Kl (51 mg, 0.31 mmol) and K₂C0₃ (2.57g, 18.6 mmol) in dry DMF (25 mL) was heated at 80 °C for 2h under nitrogen atmosphere. The reaction solution was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL) and then dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(/V-(3-(2-bromophenyl)-3- (tert-butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methylbenzofuran-3-carboxamide (3.4g, 4.7 mmol, 75 % yield) as a yellow solid.

Step 6: 6-(N-(3-(tert-butyldimethylsilyloxy)-3-(2-(4, 4, 5, 5-tetramethyl- 1, 3, 2- dioxaborolan-2- yl)phenyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran carboxamide

A solution of 6-(/V-(3-(2-bromophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methylbenzofuran-3-carboxamide (3.4 g, 4.7 mmol), bis(pinacolato)diboron (3.39 g, 9.4 mmol), potassium acetate (1.38 g, 1 1.4 mmol) and PdCI₂(dppf)-CH₂CI₂ (540 mg, 0.47 mmol) in dioxane (50 mL) was stirred at 95 °C overnight under nitrogen atmosphere. After cooling to room temperature the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL) and then dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(/V-(3-(tert- butyldimethylsilyloxy)-3-(2-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3- carboxamide (1.02 g, 1 .33 mmol, 28 % yield) as a brown solid. Step 7: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-3-yl)ethyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide

A solution of 6-(N-(3-(tert-butyldimethylsilyloxy)-3-(2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .02 g, 1.33 mmol), pyridinium 4-methylbenzenesulfonate (0.67 g, 2.66 mmol) and 1 M HCI (0.1 mL) was stirred at 30°C overnight. After the removal of solvent, the residue was dissolved in EtOAc (50 mL) and washed with H₂0 (20 mL). The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with reverse phase HPLC to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1- hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3-yl)ethyl)methylsulfonamido)-/\/- methylbenzofuran-3-carboxamide (650 mg, 1.15 mmol, 86 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.86 - 7.80 (m, 2H), 7.67 - 7.50 (d, 1 H), 7.50 - 7.41 (m, 2H), 7.35 - 7.26 (m, 2H), 7.22 - 7.14 (m, 3H), 5.83 - 5.82 (d, 1 H), 5.29 - 5.19 (m, 2H), 4.01 - 3.83 (m, 2H), 3.06 - 2.97 (m, 6H), 2.34 - 2.25 (m, 2H), 1.86 - 1.71 (m, 1 H), 1 .04 - 0.89 (m, 3H), 0.68 - 0.61 (m, 1 H). LCMS (m/z, ES⁺) = 563.1 (M+H) Example 56

5-cvclopropyl-2-(4-fluorophenyl)-6-(/\/-((1-hvdroxy-1 ,3-dihvdrobenzorciri ,2loxaborol-3- yl)methyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide

Step 1: 2-bromo-1-(2-bromophenyl)ethanone

A solution of 1-(2-bromophenyl)ethanone (20 g, 101 mmol, sigma), cuprous bromide

(9.63 g, 43.63 mmol) and silicon dioxide (100 g, 16.7mol) in EA (100 mL) and DCM (100 mL) was heated under reflux for 24h. The resulting reaction mixture was cooled to room temperature, filtered and extracted with EtOAc (200 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column chromatography to afford 2-bromo-1-(2- bromophenyl)ethanone (14 g, 50 mmol, 50 % yield) as a white solid.

Step 2: 6-(N-(2-(2-bromophenyl)-2-oxoethyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (1.5 g, 3.7 mmol), 2-bromo-1-(2-bromophenyl)ethanone (2.0 g, 7.4 mmol), potassium carbonate (1.53 g, 1 1.1 mmol) and potassium iodide (610 mg, 3.7 mmol) in DMF (50 mL) was stirred at room temperature for 4 hours. The solution was cooled to room temperature and diluted with EtOAc and water. The organic layer was dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column chromatography to afford 6-(N-(2-(2-bromophenyl)-2-oxoethyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .3 g, 2.2 mmol, 59 % yield) as a white solid. LCMS {m/z, ES⁺)= 599 (M+H)

Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-oxo-2-(2-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)phenyl)ethyl)methylsulfonamido)benzofuran-3-carboxamide

A solution of 6-(N-(2-(2-bromophenyl)-2-oxoethyl)methylsulfonamido)-5-cyclopropyl-2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .3 g, 2.2 mmol), potassium acetate (646 mg, 6.6 mmol), bis(pinacolato)diboron (1 .1 g, 4.4 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (160 mg, 0.22 mmol) in 1 ,4-dioxane (50 ml.) was degassed and refilled with nitrogen three times and heated at 100 °C overnight. The reaction solution was cooled to room

temperature. Water (100 ml.) was added and the solution was extracted with EtOAc (3 x 80 ml_). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified by column chromatography to afford 5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-6-(N-(2-oxo-2-(2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl)methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 3.0 mmol, 142% yield) as a white solid. LCMS (m/z, ES⁺)= 647 (M+H)

Step 4: 6-(N-(2-(2-bromophenyl)-2-hydroxyethyl)methylsulfonamido)-5-cyclopropyl-2- (4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of 6-(N-(2-(2-bromophenyl)-2-oxoethyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (2.0 g, 3.44 mmol ) in THF (40 ml.) and MeOH (10 ml.) was added NaBH₄ (0.57 g, 13.35 mmol) in portions and then stirred at room temperature for 3 hours. The reaction mixture was quenched with water (25 ml), extracted with EtOAc (3 x 30 ml), washed with brine (50 ml.) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified by column chromatography (EA : PE = 1 :2) to afford 6-(N-(2-(2-bromophenyl)-2- hydroxyethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (500 mg, 0.83 mmol, 26 % yield) as a white solid. Step 5: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-( ( 1-hydroxy-1, 3-dihydrobenzo[c][ 1, 2]oxaborol- 3-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

A solution of 6-(N-(2-(2-bromophenyl)-2-hydroxyethyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.5 g, 0.83 mmol), bis(pinacolato)diboron (0.421 g, 1.66 mmol), potassium acetate (0.244 g, 2.49 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (92 mg, 0.08 mmol) in dioxane (30 mL) was heated at 80 °C overnight under a nitrogen atmosphere. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by pre-HPLC to afford 5- cyclopropyl-2-(4-fluorophenyl)-6-(N-((1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (42 mg, 0.07 mmol, 9 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.94 - 7.87 (m, 2H), 7.70 - 7.61 (m, 2H), 7.4 - 7.09 (m, 4H), 5.40 - 5.29 (m, 1 H), 4.48 - 3.70 (m, 2H), 3.18 - 2.93 (m, 6H), 2.44 - 2.30 (m, 1 H), 1 .15 - 0.96 (m, 3H), 0.80 - 0.72 (m, 1 H). LCMS (m/z, ES+)= 549.1 (M+H)

Example 57

5-cvclopropyl-2-(4-fluorophenyl)-6-(/\/-((1-hvdroxy-7-(trifluoromethyl)-1 ,3- dihvdrobenzorcir^'/^loxaborol-S-vDmethvDmethylsulfonamidoV/V-methylbenzofuran-S- carboxamide

Step 1: 4-methyl-2-(trifluoromethyl)benzenamine

A solution of 4-methyl-1-nitro-2-(trifluoromethyl)benzene (6.0 g, 29 mmol, Alfa), 10% Pd/C (0.6 g) and HCI (1 N aq., 1.45ml, 1.45 mmol) in EtOAc (50 mL) was stirred at 25 °C under 0.3 MPa of hydrogen overnight. The reaction mixture was filtered and evaporated under reduced pressure to afford the crude 4-methyl-2-(trifluoromethyl)benzenamine (5.2 g, 30 mmol, 101 % yield) as a colorless oil.

Step 2: 2-bromo-4-methyl-6-(trifluoromethyl)benzenamine

To a solution of 4-methyl-2-(trifluoromethyl)benzenamine (5.2 g, 30 mmol) in acetic acid (50 mL) was added NBS (5.87 g, 33 mmol) in portions at 15 °C under nitrogen atmosphere. Then, the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 150 mL) and Na₂C0₃ (10% aq. 150 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 2-bromo-4-methyl-6- (trifluoromethyl)benzenamine (5.29 g, 21.2 mmol, 70 % yield) as a yellow solid.

Step 3: methyl 2-amino-5-methyl-3-(trifluoromethyl)benzoate

A solution of 2-bromo-4-methyl-6-(trifluoromethyl)benzenamine (5.27 g, 21 mmol),

Pd(OAc)₂ (0.94 g, 4.2 mmol), dppf (3.49 g, 6.3 mmol) and Et₃N (2.23 g, 22 mmol) in DMSO (120 mL) and MeOH (80 mL) was heated at 80 °C for 16 hours under 2.0 MPa of carbon monoxide. The reaction mixture was cooled down to room temperature and filtered. The filtrate was diluted with EtOAc (400 mL), washed with water (3 x 300 mL) and brine (300 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford methyl 2-amino-5-methyl-3- (trifluoromethyl)benzoate (4.35 g, 18.7 mmol, 90 % yield) as a white solid.

Step 4: methyl 2-bromo-5-methyl-3-(trifluoromethyl)benzoate

To a solution of methyl 2-amino-5-methyl-3-(trifluoromethyl)benzoate (4.35 g, 18.7 mmol) in MeCN (25mL) was added HBr (47% aq. 23.1 mL) drop wise at 0 °C over 10 minutes. Then, NaN0₂ (1 .42 g, 20.6 mmol) in water (5 mL) was added drop wise over 1 hour at 0 °C. After the addition, the solution was stirred for 5 minutes at 0 °C followed by the addition of CuBr (3.12 g, 21.5 mmol) in portions over 30 minutes. The mixture was heated at 70 °C for 1 hour. After cooling to 0 °C, water (40 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with cold water (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford methyl 2-bromo-5-methyl-3- (trifluoromethyl)benzoate (4.95 g, 16.6 mmol, 89 % yield) as a white solid.

Step 5: methyl 2-bromo-5-(bromomethyl)-3-(trifluoromethyl)benzoate

A solution of methyl 2-bromo-5-methyl-3-(trifluoromethyl)benzoate (1 .94 g, 6.53 mmol), benzoyl peroxide (8 mg, 0.03 mmol) and /V-bromosuccinimide (1 .28 g, 7.18 mmol) in 25 mL of CCI₄ was heated under reflux for 24 hours. The reaction solution was cooled down and concentrated under reduced pressure. The residue was purified with column

chromatography to afford methyl 2-bromo-5-(bromomethyl)-3-(trifluoromethyl)benzoate (1 .8 g, 4.8 mmol, 85 % yield) as a white solid.

Step 6: methyl 2-bromo-6-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-3-(trifluoromethyl)benzoate A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (500 mg, 1 .24mmol), methyl 2-bromo-5-

(bromomethyl)-3-(trifluoromethyl)benzoate (932 mg, 2.24 mmol), Kl (10 mg, 0.06 mmol) and K₂C0₃ (513 mg, 3.72 mmol) in dry DMF (15 mL) was stirred at room temperature for 1 hour under nitrogen. The reaction mixture was diluted with water (45 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and then dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford methyl 2-bromo-6-((N-(5- cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-(trifluoromethyl)benzoate (520 mg, 0.75 mmol, 60 % yield) as a yellow solid.

Step 7: methyl 6-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo furan-6- yl)methylsulfonamido)methyl)-2-(4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-3- ( trifluorome thyl)benzoa te

A solution of methyl 2-bromo-6-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-3-(trifluoromethyl)benzoate (450 mg, 0.64 mmol), bis(pinacolato)diboron (325 mg, 1 .28 mmol), potassium acetate (188 mg, 1 .92 mmol) and PdCI₂(dppf)-CH₂CI₂ (69 mg, 0.06 mmol) in dioxane (25 mL) was degassed and refilled with nitrogen three times and then heated at 100 °C overnight. After cooling down to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with reverse phase HPLC to afford methyl 6-((N- (5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)benzoate (15 mg, 0.02 mmol, 3 % yield) as a white solid.

Step 8: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((1-hydroxy-7-(trifluoromethyl)-1,3- dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide

To a solution of methyl 6-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-(trifluoromethyl)benzoate (15mg, 0.02 mmol ) in THF (5 mL) was added LiBH₄ (2M in THF, 0.03 mL, 0.06 mmol) dropwise at -5°C. After the addition, the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into ice water (55 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂S0_4. After the removal of solvent, the residue was purified with pre-HPLC to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((1 - hydroxy-7-(trifluoromethyl)-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5-yl)methyl)methylsulfonamido)- A/-methylbenzofuran-3-carboxamide (5 mg, 0.008 mmol, 40 % yield) as a white solid. ¹ H

NMR (METHANOL-d₄) δ: 7.85 - 7.80 (m, 2H), 7.52 - 7.47 (d, 2H), 7.27 - 7.15 (m, 4H), 5.74 - 5.72 (d, 1 H), 5.06 - 5.03 (m, 4H), 3.05 - 2.97 (m, 6H), 2.22 - 2.13 (m, 1 H), 1.06 - 1.03 (m, 1 H), 0.90 - 0.85 (m, 2H), 0.53 - 0.51 (m, 1 H). LCMS (m/z, ES⁺)= 617.2 (M+H). Example 58 & 59

5-cvclopropyl-2-(4-fluorophenyl)-6-[{2-[(3S)-1 -hvdroxy-1 ,3-dihydro-2, 1-benzoxaborol-3- yllethyl}(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide & 5-cyclopropyl-2-(4- fluorophenyl)-6-r{2-r(3f?)-1-hvdroxy-1,3-dihvdro-2,1-benzoxaborol-3- yllethyl}(methylsulfonyl)aminol-/V-methyl-1-benzofuran-3-carboxamide

Racemic 5-cyclopropyl-2-(4-fluorophenyl)-6-[{2-1-hydroxy-1,3-dihydro-2,1- benzoxaborol-3-yl]ethyl}(methylsulfonyl)amino]-/V-methyl-1-benzofuran-3-carboxam was resolved using supercritical C0₂ column chromatography with a chiral stationary phase: 10% MeOH(10% CHCI₃)/C0₂140 bars 40°C 2 mL/min OJ-H. Absolute configuration was assigned based on VCD spectroscopy; Theory Level: ONIOM method, b3pw 91/6-311 +g (2df) applied to S0₂ with B3LYP/6-311 G(d,p) applied to the rest of the molecule.

Enantiomer#1 (3S): ¹H NMR (METHANOL-d₄) δ: 7.84 - 7.92 (m, 3H), 7.68 (d, J = 16.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.34-7.41 (m, 1H), 7.15-7.31 (m, 4H), 7.13 (s, 1H), 5.19- 5.31 (m, 1H), 3.73- 4.09 (m, 2H), 3.09 (d, J = 9.2 Hz, 3H), 2.91 (s, 3H), 2.18 - 2.48 (m, 2H), 1.56 - 1.81 (m, 1 H), 0.80 - 1.09 (m, 3H), 0.48 - 0.70 (m, 1 H). LCMS {m/z, ES⁺) = 563 (M+H) Enantiomer#2 {3R): ¹H NMR (METHANOL-d₄) δ: 8.42 (d, J = 4.5 Hz, 1H), 7.83 - 7.93 (m, 3H), 7.68 (d, J = 16.6 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.33 - 7.41 (m, 1H), 7.15 - 7.31 (m, 4H), 7.13 (s, 1H), 5.18 - 5.32 (m, 1H), 3.85 - 4.08 (m, 2H), 3.09 (d, J = 9.4 Hz, 3H), 2.85 - 2.94 (m, 3H), 2.18-2.48 (m, 2H), 1.56-1.81 (m, 1H), 0.85- 1.07 (m, 3H), 0.49-0.69 (m, 1H). 563 (M+H). LCMS {m/z, ES⁺) = 563 (M + H).

Example 60

5-Cvclopropyl-2-(4-fluorophenyl)-6-r({1-hvdroxy-7-r(trifluoromethyl)oxyl-1,3-dihvdro-2,1- benzoxaborol-5- l}methyl)(methylsulfonyl)aminol-/\/-methyl-1-benzofuran-3-carboxamide

Step 1: {4-Methyl-2-[(trifluoromethyl)oxy]phenyl}amine

A mixture of 4-bromo-2-[(trifluoromethyl)oxy]aniline (20.0 g, 78 mmol), PdCI₂(dppf)- CH₂CI₂ adduct (3.19 g, 3.91 mmol), and trimethyl boroxine (24.5 g, 195 mmol) in 1,4-dioxane (300 mL) was degassed, then heated to an internal temperature of 80°C for 1 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% dichloromethane in hexanes) afforded {4-methyl-2-[(trifluoromethyl)oxy]phenyl}amine (13.36 g, 89%) as a colorless oil. ¹H NMR (CHLOROFORM-d) δ: 6.96 (s, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 6.72 (d, J = 8.1 Hz, 1 H), 3.79 (br. s., 2H), 2.26 (s, 3H).

Step 2: {2-Bromo-4-methyl-6-[(trifluoromethyl)oxy]phenyl}amine

A solution of {4-methyl-2-[(trifluoromethyl)oxy]phenyl}amine (12.20 g, 63.8 mmol) in acetonitrile (100 mL) was cooled to 0°C. To this was added NBS (1 1.93 g, 67.0 mmol) in portions over 10 minutes. After 30 minutes, the reaction mixture was diluted with water and ethyl acetate, then stirred for 1 hour. After additional dilution with water and ethyl acetate, the layers were separated. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (1 x) and brine (1x), then dried over sodium sulfate and concentrated to afford {2-bromo-4-methyl-6-

[(trifluoromethyl)oxy]phenyl}amine (17.32 g, 100% yield) as a dark red oil. ¹ H NMR

(CHLOROFORM-d) δ: 7.19 (s, 1 H), 6.94 (s, 1 H), 2.25 (s, 3H).

Step 3: Methyl 2-amino-5-methyl-3-[(trifluoromethyl)oxy]benzoate

A mixture of {2-bromo-4-methyl-6-[(trifluoromethyl)oxy]phenyl}amine (17.32 g, 64.1 mmol), dppf (3.20 g, 5.77 mmol), triethylamine (1 1 .2 mL, 80 mmol), and palladium acetate (0.86 g, 3.85 mmol) in 1 :1 methanol/DMSO (120 mL) was pressurized to 60 psi with carbon monoxide and heated in an 80°C bath for 22 hours, adding additional carbon monoxide when the pressure dropped over the first 6 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite, rinsing thoroughly with ethyl acetate. The filtrate was washed with brine (2x), then dried over sodium sulfate and concentrated.

Purification by silica gel chromatography (0 to 30% ethyl acetate in hexanes) afforded methyl 2-amino-5-methyl-3-[(trifluoromethyl)oxy]benzoate (1 1 .98 g, 75%) as a yellow oil. ¹H NMR (CHLOROFORM-d) δ: 7.63 (d, J = 1 .1 Hz, 1 H), 7.13 (s, 1 H), 5.40 - 6.09 (m, 2H), 3.89 (s, 3H), 2.26 (s, 3H). LCMS {m/z, ES⁺) = 250 (M+H).

Step 4: Methyl 2-bromo-5-methyl-3-[(trifluoromethyl)oxy]benzoate

A solution of methyl 2-amino-5-methyl-3-[(trifluoromethyl)oxy]benzoate (13.1 g, 52.6 mmol) in acetonitrile (200 mL) was cooled to -5°C and treated with concentrated aqueous HBr (65 mL, 47%) over 30 min. A solution of sodium nitrite (4.53 g, 65.7 mmol) in 20 mL water was added drop wise over 30 min, keeping the temperature below 0°C. To this was added copper bromide (9.80 g, 68.3 mmol) in portions over 15 minutes. After another 15 minutes, the reaction mixture was allowed to warm to room temperature, and then was heated slowly to an internal temperature of 75°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water (1 x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 20% ethyl acetate in hexanes) afforded methyl

2- bromo-5-methyl-3-[(trifluoromethyl)oxy]benzoate (9.79 g, 60%) as a yellow oil. Impure fractions containing a slightly higher R_f impurity afforded another 4.82 g (29%, 80% pure) of the product. ¹H NMR (CHLOROFORM-d) δ: 7.48 (s, 1 H), 7.25 (br.s., 1 H), 3.95 (s, 1 H), 2.38 (s, 3H).

Step 5: Methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}-3-[(trifluoro

A solution of methyl 2-bromo-5-methyl-3-[(trifluoromethyl)oxy]benzoate (5.46 g, 17.44 mmol) in 1 ,2-dichloroethane (250 mL) was treated with NBS (3.72 g, 20.93 mmol) and benzoyl peroxide (0.21 g, 0.87 mmol) and heated under reflux for 21 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane, then washed with water (2x). The organic layer was washed with brine (1x), dried over sodium sulfate and concentrated to afford 6.61 g of a reddish solid which contains approximately 33% of the desired methyl 2-bromo-5-(bromomethyl)-3-[(trifluoromethyl)oxy]benzoate by LC/MS. A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-

3- carboxamide (0.75 g, 0.86 mmol), methyl 2-bromo-5-(bromomethyl)-3- [(trifluoromethyl)oxy]benzoate (3.3 g of crude product above), 1 .86 mmol) and potassium carbonate (0.52 g, 3.73 mmol) in acetonitrile (25 mL) was heated to 60° for 1 .5 h, at which point the temperature was increased to 70° for 2.5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}-3-[(trifluoromethyl)oxy]benzoate (0.50 g, 37%) as an orange oil. ¹H NMR (DMSO-d₆) δ: 8.41 (m, 1 H), 7.89 - 7.98 (m, 2H), 7.82 - 7.89 (m, 1 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.56 (s, 1 H), 7.33 - 7.45 (m, 2H), 6.88 - 6.95 (m, 1 H), 5.01 - 5.13 (m, 1 H), 4.76 - 4.88 (m, 1 H), 3.78 - 3.89 (m, 3H), 3.22 - 3.30 (m, 3H), 2.73 - 2.87 (m, 3H), 2.08 - 2.25 (m, 1 H), 0.71 - 1 .00 (m, 2H), 0.49 - 0.66 (m, 1 H), 0.02 - 0.23 (m, 1 H). LCMS {m/z, ES⁺) = 713 (M+H). Step 6: 6-[({4-Bromo-3-(hydroxymethyl)-5-

[(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2- N-methyl-1-benzofuran-3-carboxamide

A solution of methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}-3-

[(trifluoromethyl)oxy]benzoate (0.50 g, 0.70 mmol) in tetrahydrofuran (10 ml.) and methanol (1 ml.) was cooled in an ice bath and treated with lithium borohydride (0.88 ml_, 1 .75 mmol, 2.0 M in THF). After 30 min, the reaction was allowed to warm to rt and was stirred for an additional 1 h. The reaction was quenched with 1 N sodium hydroxide, stirred for 10 minutes, then diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[({4-bromo-3- (hydroxymethyl)-5-[(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl- 2-(4-fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (0.34 g, 71 %) as a gold solid. ¹H NMR (DMSO-de) δ: 8.41 (m, 1 H), 7.89 - 7.99 (m, 2H), 7.83 - 7.89 (m, 1 H), 7.51 (m, 1 H), 7.34 - 7.44 (m, 2H), 7.27 (s, 1 H), 6.92 (s, 1 H), 5.62 (t, J = 5.5 Hz, 1 H), 5.02 (d, J = 14.6 Hz, 1 H), 4.84 (d, J = 14.6 Hz, 1 H), 4.42 - 4.55 (m, 2H), 3.18 - 3.28 (m, 3H), 2.75 - 2.89 (m, 3H), 2.14 - 2.29 (m, 1 H), 0.50 - 1.01 (m, 3H), 0.08 - 0.28 (m, 1 H). LCMS {m/z, ES⁺) = 685 (M+H). Step 7: 6-[({4-Bromo-3-({[(methyloxy)methyl]oxy}methyl)-5-

A solution of 6-[({4-bromo-3-(hydroxymethyl)-5- [(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)- A/-methyl-1-benzofuran-3-carboxamide (0.34 g, 0.50 mmol) in THF (10 ml.) was treated with DIEA (0.26 ml_, 1 .49 mmol) and chloromethyl methyl ether (0.1 1 ml_, 1 .49 mmol), then heated in a 50° bath for 22 hours. The reaction was cooled to room temperature and diluted with water, then extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel

chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[({4-bromo-3- ({[(methyloxy)methyl]oxy}methyl)-5-

[(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)- A/-methyl-1-benzofuran-3-carboxamide (0.30 g, 83%) as a gold glass. ¹H NMR (DMSO-d₆) δ: 8.34 - 8.45 (m, 1 H), 7.88 - 7.97 (m, 2H), 7.81 - 7.87 (m, 1 H), 7.31 - 7.45 (m, 4H), 6.87 - 6.94 (m, 1 H), 5.01 (d, J = 14.4 Hz, 1 H), 4.84 (d, J = 14.5 Hz, 1 H), 4.59 - 4.66 (m, 2H), 4.53 (s,

2H), 3.14 - 3.28 (m, 6H), 2.72 - 2.88 (m, 3H), 2.10 - 2.27 (m, 1 H), 0.53 - 0.98 (m, 3H), 0.08 - 0.27 (m, 1 H). LCMS {m/z, ES⁺) = 729 (M+H). Step 8: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[({1-hydroxy-7-[(trifluorome

2, 1-benzoxaborol-5-yl}methyl)(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxam A mixture of 6-[({4-bromo-3-({[(methyloxy)methyl]oxy}methyl)-5- [(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)- A/-methyl-1-benzofuran-3-carboxamide (0.28 g, 0.38 mmol), potassium acetate (75 mg, 0.77 mmol), bis(pinacolato)diboron (146 mg, 0.58 mmol), sodium bromide (39 mg, 0.38 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (28 mg, 0.038 mmol) in 1 ,4-dioxane (10 ml.) in a thick-walled glass pressure vessel was degassed, then heated at 95°C with stirring for 20 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[({3- ({[(methyloxy)methyl]oxy}methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- [(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (0.29 g, 71 % pure by LC/MS) as a gold oil. This oil was dissolved in THF (15 ml.) and treated with 1 N HCI (5 ml_), then heated under reflux. After 16 h, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane), then a second purification by reverse phase HPLC followed by lyophilization afforded 5-cyclopropyl-2-(4-fluorophenyl)- 6-[({1-hydroxy-7-[(trifluoromethyl)oxy]-1 ,3-dihydro-2, 1-benzoxaborol-5- yl}methyl)(methylsulfonyl)amino]-/\/-methyl-1-benzofuran-3-carboxamide (41.4 mg, 17% over 2 steps) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.80 - 7.91 (m, 2H), 7.57 (s, 1 H), 7.14 - 7.26 (m, 3H), 7.08 (m, 1 H), 6.98 (s, 1 H), 4.81 - 5.05 (m, 4H), 3.13 (s, 3H), 2.88 (s, 3H), 2.16 (m, 1 H), 0.84 - 1 .04 (m, 1 H), 0.59 - 0.84 (m, 2H), 0.17 - 0.37 (m, 1 H). LCMS {m/z, ES⁺) = 633 (M+H).

Example 61

6-(N-(2-(7-chloro-1 -hvdroxy-1 ,3-dihvdrobenzorciri ,2loxaborol-3-yl)ethyl)methylsulfonamido)- 5-cvclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: 1-(2-bromo-3-chlorophenyl)prop-2-en-1-ol

To a solution of 2-bromo-3-chlorobenzaldehyde (3 g, 13.7 mmol, Ouhe) in dry THF (100 mL) was added vinylmagnesium bromide (15 mL, 1 M) at -50°C under nitrogen atmosphere and the reaction solution was stirred at rt for 2h. The reaction was quenched with ammonium chloride (sat. aq., 20 mL) and extracted with EtOAc (3 ^χ 50 mL). The combined organic layers were washed with NaHC0₃ (sat. aq.) and brine (aq) and then dried over anhydrous Na₂S0₄. After the removal of solvent, it afforded 1-(2-bromo-3- chlorophenyl)prop-2-en-1 -ol (3.5 g, 14.17 mmol, quant., crude) as a colorless oil.

Step 2: (1-(2-bromo-3-chlorophenyl)allyloxy)(tert-butyl)dimethylsilane

To a solution of 1-(2-bromo-3-chlorophenyl)prop-2-en-1-ol (3.5 g, 14.17 mmol) and imidazole (2.41 g, 35.43 mmol) in dry DMF (20 mL) was added the TBSCI (3.2 g, 21 .25 mmol) in DMF (10 mL) at 5 °C under nitrogen atmosphere. Then, the reaction solution was stirred at room temperature for 30 minutes. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 ^χ 50 mL). The combined organic layers were washed with NaHC0₃ (sat. aq.) and brine (sat. aq.) and then dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford (1 - (2-bromo-3-chlorophenyl)allyloxy)(tert-butyl)dimethylsilane (4 g, 1 1 .05 mmol, 78%) as a colorless oil.

Step 3: 3-(2-bromo-3-chlorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol

A solution of (1-(2-bromo-3-chlorophenyl)allyloxy)(tert-butyl)dimethylsilane (4 g, 1 1.05 mmol) and 9-BBN dimer (2.97 g, 12.15 mmol) in dry THF (80 mL) was stirred at room temperature for 4 hours under nitrogen atmosphere. Then, NaOH (3N aq., 40 mL) was added at 0 °C followed by the addition of hydrogen peroxide (30%, 40 mL). The reaction was stirred at room temperature for 1 .5 hours and extracted with EtOAc (3 ^χ 50 mL). The combined organic layers were washed with water and brine (aq.) and then dried over anhydrous Na₂S0₄. After the removal of solvent, the crude was purified with column chromatography to afford 3-(2-bromo-3-chlorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1 - ol (3.3 g, 8.73 mmol, 79%) as a colorless oil. Step 4: (3-bromo-1-(2-bromo-3-chlorophenyl)propoxy)(tert-butyl)dimethylsilane

To a solution of 3-(2-bromo-3-chlorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol (3.3 g, 8.73 mmol) and Ph₃P (4.57 g, 17.46 mmol) in dry DCM (50 mL) was added NBS (3.26 g, 18.333 mmol) at 0 °C under nitrogen atmosphere and the reaction solution was stirred at room temperature for 1 hour. The reaction was quenched with water (40 mL). The separated organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford (3-bromo-1 -(2-bromo-3- chlorophenyl)propoxy)(tert-butyl)dimethylsilane (3.3 g, 7.62 mmol, 87%) as a colorless oil.

Step 5: 6-(N-(3-(2-bromo-3-chlorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (1 g, 2.485 mmol), (3-bromo-1 -(2-bromo-3- chlorophenyl)propoxy)(tert-butyl)dimethylsilane (1.39 g, 3.23 mmol), potassium carbonate (1 .03 g, 7.455 mmol) and Kl (0.41 g, 2.485 mmol) in dry DMF (15 mL) was heated at 80 °C for 2 hours under a nitrogen atmosphere. The reaction was quenched with water (50mL). After filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(N-(3-(2-bromo-3-chlorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .4 g, 1 .83 mmol, 73%) as a brown solid. Step 6: 6-(N-(3-(2-bromo-3-chlorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl-

2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 6-(/V-(3-(2-bromo-3-chlorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methylbenzofuran-3-carboxamide (1 .3 g, 1.70 mmol) and HCI (5N aq., 12.5 mL) in dry THF (30 mL) was heated at 40 °C overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature and extracted with EtOAc (3 ^χ 50 mL). The combined organic layers were washed with water and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(N-(3-(2-bromo-

3- chlorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (0.85 g, 1.31 mmol, 77%) as a brown solid. Step 7: 6-(N-(2-(7-chloro- 1 -hydroxy- 1, 3-dihydrobenzo[c][ 1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide

A solution of 6-(/V-(3-(2-bromo-3-chlorophenyl)-3-hydroxypropyl)methylsulfonamido)- 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide (0.85 g, 1 .31 mmol), bis(pinacolato)diboron (0.665 g, 2.62 mmol), potassium acetate (385 mg, 3.93 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (151 mg, 0.131 mmol) in dioxane (25 mL) was heated at 98 °C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with pre- HPLC to afford 6-(/V-(2-(7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3- carboxamide (55 mg, 0.092 mmol, 7%) as a white solid. ¹ H NMR (300MHz, Methanol_d4) δ: 7.94 - 7.89 (m, 2 H), 7.72 - 7.69 (d, 1 H), 7.37 - 7.1 1 (m, 6 H), 5.33 - 5.30 (m, 1 H), 3.97 - 3.92 (m, 2 H), 3.13 - 3.1 1 (d, 3 H), 2.94 (s, 3 H), 2.49 - 2.22 (m, 2 H), 1 .89 - 1.76 (m, 1 H), 1.08 - 1.01 (m, 3 H), 0.91 - 0.69 (m, 1 H). LCMS(m/z, ES⁺)= 597.1 (M+H).

Example 62

5-cvclopropyl-6-[[(7-fluoro-1 -hvdroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyll(methylsulfonyl)aminol-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide

Step 1: methyl 5-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-6- yl](methyl sulfonyl)amino]methyl}-2-bromo-3-fluorobenzoate

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran- 3-carboxamide (1 .561 g, 4.02 mmol), methyl 2-bromo-5-(bromomethyl)-3-fluorobenzoate (1 .31 g, 4.02 mmol), K₂C0₃ (0.666 g, 4.82 mmol), and Nal (0.060 g, 0.402 mmol) in DMF (6 mL) was heated to 30°C for 40 minutes, diluted with water, extracted with EtOAc, and the organic phase was dried over Na₂S0₄, filtered, concentrated, and purified by column chromatography to give methyl 5-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)-1 - benzofuran-6-yl](methylsulfonyl)amino] methyl}-2-bromo-3-fluorobenzoate (2.43 g, 3.84 mmol, 95 % yield) as a pale yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.87 - 7.94 (m, 2 H), 7.46 (s, 1 H), 7.36 (s, 1 H), 7.30 (s, 1 H), 7.16 - 7.25 (m, 3 H), 5.74 (br. s., 2 H), 4.96 (d, 1 H), 4.77 (d, 1 H), 3.90 (s, 3 H), 3.06 (s, 3 H), 2.16 (s, 1 H), 1 .01 - 1 .12 (m, 1 H), 0.88 - 1.01 (m, 2 H), 0.52 - 0.63 (m, 1 H).

Step 2: 6-[{[4-bromo-3-fluoro-5-(hydroxymethyl)phenyl]methyl} (methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)- 1-benzofuran-3-carboxamide

To a solution of methyl 5-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)-1 - benzofuran-6-yl](methylsulfonyl)amino]methyl}-2-bromo-3-fluorobenzoate (2.4g, 3.79 mmol) in THF (12 ml_) and methanol (2 mL) was added 14ml_ 2M THF solution of lithium borohydride (26.53 mmol) drop wise at room temperature. After the addition, the solution was stirred under room temperature until all the starting material was completely consumed. The solution was quenched with water, extracted with EtOAc, washed with brine, and the organic layer was collected, dried over sodium sulfate, filtered, and concentrated to give 6- [{[4-bromo-3-fluoro-5-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2- (4-fluorophenyl)-1 -benzofuran-3-carboxamide (1.66g, 2.74 mmol, 72.4 % yield) as a white foam. ¹ H NMR (400 MHz, CHLOROFORM-d) δ: 7.91 (dd, J=8.8, 5.3 Hz, 2 H), 7.36 (s, 1 H), 7.31 (s, 1 H), 7.16 - 7.24 (m, 3 H), 7.05 (dd, J=8.6, 1.4 Hz, 1 H), 5.69 (br. s., 2 H), 4.93 - 5.02 (m, 1 H), 4.75 (d, J=14.4 Hz, 1 H), 4.71 (s, 2 H), 3.05 (s, 3 H), 2.13 - 2.24 (m, 1 H), 1 .03 - 1.13 (m, 1 H), 0.87 - 1.03 (m, 2 H), 0.59 (d, J=5.7 Hz, 1 H). Step 3: 6-[{[4-bromo-3-fluoro-5-

({[(methyloxy)methyl]oxy}methyl)phenyl]methyl}(methylsulfonyl) amino]-5-cyclopropyl-2-(4- fluorophenyl)-1-benzofuran-3-carboxamide

To a solution of 6-[{[4-bromo-3-fluoro-5- (hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1 - benzofuran-3-carboxamide (1 .65g, 2.73 mmol) in THF (10 mL) and DMF (1 mL) was added Hunigs' base (0.570 mL, 3.27 mmol). The solution was then treated with chloromethyl methyl ether (0.248 mL, 3.27 mmol) at room temperature. After the addition, the resulting solution was heated up to 60°C with stirring overnight. The solution was washed with water, extracted with EtOAc, dried over sodium sulfate, filtered , concentrated and purified by column chromatography to give 6-[{[4-bromo-3-fluoro-5-({[(methyloxy)methyl]oxy}methyl)phenyl] methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1 -benzofuran-3-carboxamide (1 .39g, 2.140 mmol, 79 % yield) as a colorless oil.

Step 4: 5-cyclopropyl-6-[{[3-fluoro-5-({[(methyloxy)methyl]oxy}methyl)-4-(4,4, 5, 5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]methyl} (methylsulfonyl)amino]-2-(4-fluorophenyl)-1- benzofuran-3-carboxamide To a mixture of 6-[{[4-bromo-3-fluoro-5-({[(methyloxy)methyl]oxy}methyl)phenyl]methyl} (methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide (1 .35g, 2.079 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (1 .056 g, 4.16 mmol), and KOAc (0.612 g, 6.24 mmol) in 1 ,4-dioxane (10 mL) was added Pd(Cy₃)₂CI₂ (0.153 g, 0.208 mmol) under N₂. The mixture was heated at 80°C overnight. The mixture was filtered through celite and the solids were washed with EtOAc. The filtrated was and purified by column chromatography to give 5-cyclopropyl-6-[{[3-fluoro-5- ({[(methyloxy)methyl]oxy}methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl} (methylsulfonyl)amino]-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide (0.9g, 1.292 mmol, 62.2 % yield) as a colorless oil. LC-MS (m/z, ES⁺)=697 (M+H).

Step 5: 5-cyclopropyl-6-[[(7-fluoro-1-hydroxy-1,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-6-[{[3-fluoro-5-({[(methyloxy)methyl]oxy}methyl)-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-fluorophenyl)- 1-benzofuran-3-carboxamide (0.9g, 1.292 mmol) and 6N HCI (2 mL, 1 .292 mmol) in THF (8 mL) was heated to 60°C for 4hours. The solution was extracted with EtOAc and the organic layer was concentrated and purified by reverse phase HPLC to give 5-cyclopropyl-6-[[(7- fluoro-1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5-yl)methyl](methylsulfonyl)amino]-2-(4- fluorophenyl)-1 -benzofuran-3-carboxamide (0.250g, 0.453 mmol, 35.0 % yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.26 (br. s., 1 H), 7.91 - 8.04 (m, 3 H), 7.79 - 7.90 (m, 1 H), 7.70 (br. s., 1 H), 7.38 (t, J=8.5 Hz, 2 H), 7.18 (br. s., 1 H), 6.96 (br. s., 2 H), 5.02 (d, J=14.6 Hz, 1 H), 4.93 (br. s., 2 H), 4.85 (d, J=14.6 Hz, 1 H), 3.24 (br. s., 3 H), 2.29 (br. s., 1 H), 0.94 (br. s., 1 H), 0.80 (br. s., 2 H), 0.22 (br. s., 1 H). LC-MS (m/z, ES⁺)=553 (M+H).

Example 63

5-cvclopropyl-6-(/\/-(2-(7-fluoro-1-hvdroxy-1 ,3-dihvdrobenzorcin ,2loxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: 1-(2-bromo-3-fluorophenyl)prop-2-en-1-ol To a solution of 2-bromo-3-fluorobenzaldehyde (5 g, 24.63 mmol, Ouhe) in dry THF (120 mL) was added vinylmagnesium bromide (27 mL, 1 M) at -50 °C under nitrogen atmosphere and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched with ammonium chloride (saturated aq., 20 mL) and water (20 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with saturated NaHC0₃ (aq.) and brine and then dried over anhydrous Na₂S0₄. Removal of the solvent affords 1 -(2-bromo-3-fluorophenyl)prop-2-en-1 -ol (5.68 g, 24.63 mmol, 99%) as a colorless oil. Step 2: (1-(2-bromo-3-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane

To a solution of 1-(2-bromo-3-fluorophenyl)prop-2-en-1 -ol (5.68 g, 24.63 mmol) and imidazole (4.188 g, 61 .58 mmol) in dry DMF (20 mL) was added TBSCI (5.56 g, 36.95 mmol) in DMF (10 mL) at 5 °C under nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. The reaction solution was quenched with water (150 mL) and extracted with EtOAc (3x150 mL). The organic solution was washed with NaHC0₃ (sat. aq) and brine and then dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford (1-(2-bromo-3-fluorophenyl)allyloxy)(tert- butyl)dimethylsilane (8g, 23.19 mmol, 94%) as a colorless oil. Step 3: 3-(2-bromo-3-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol

A solution of (1-(2-bromo-3-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane (8g, 23.19 mmol) and 9-BBN (74.2 mL, 0.5M in THF) in dry THF (160 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The reaction solution was quenched with NaOH (3N aq., 120 mL) at 0 °C followed by the addition of hydrogen peroxide (30%, 80 ml). The reaction solution was stirred at room temperature for 4 hours at room temperature and then extracted with EtOAc (3x150 mL). The combined organic layers were washed with water and brine and dried over anhydrous Na₂S0_4. After the removal of solvent, the residue was purified with column chromatography to afford 3-(2-bromo-3-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propan-1-ol (8.2 g, 22.59 mmol, 97%) as a colorless oil.

Step 4: (3-bromo-1-(2-bromo-3-fluorophenyl)propoxy)(tert-butyl)dimethylsilane

To a solution of 3-(2-bromo-3-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol (802 g, 22.59 mmol) and Ph₃P (7.12 g, 27.1 1 mmol) in dry DCM (90 mL) was added NBS (6.03 g, 33.88 mmol) at 0 °C under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with water

(50mL) and the organic layer was dried over anhydrous Na₂S0_4. After removal of solvent, the residue was purified with column chromatography to afford (3-bromo-1 -(2-bromo-3- fluorophenyl)propoxy)(tert-butyl)dimethylsilan(7.8 g, 18.3 mmol, 80%) as a colorless oil.

Step 5: 6-(N-(3-(2-bromo-3-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N^ methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (1 g, 2.485 mmol), (3-bromo-1 -(2-bromo-3- fluorophenyl)propoxy)(tert-butyl)dimethylsilane (1.6 g, 3.73 mmol), potassium carbonate (1 .03 g, 7.455 mmol) and Kl (0.41 g, 2.485 mmol) in dry DMF (10 mL) was heated at 80 °C for 2 hours under a nitrogen atmosphere. The reaction solution was quenched with water (50ml_). After filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(N-(3-(2-bromo-3-fluorophenyl)-3-(ferf- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .7 g, 2.27 mmol, 91 %) as a brown solid.

Step 6: 6-(N-(3-(2-bromo-3-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl-

2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 6-(/V-(3-(2-bromo-3-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (2.05 g, 2.741 mmol) and HCI (5N aq., 20 mL) in dry THF (40 mL) was heated at 40 °C overnight under nitrogen atmosphere. The reaction solution was cooled to room temperature and extracted with EtOAc (3x50 mL). The combined organic layers were washed with water and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(N-(3-(2-bromo-

3- fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .2 g, 1 .9 mmol, 70%) as a brown solid. Step 7: 5-cyclopropyl-6-(N-(2-(7-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxa

A solution of 6-(/V-(3-(2-bromo-3-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide (1 .2 g, 1.9 mmol), bis(pinacolato)diboron (1 .93 g, 7.6 mmol), potassium fluoride (200 mg, 3.44 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (219 mg, 0.19 mmol) in dioxane (25 mL) was heated at 120 °C for 1.5 h under nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford 5-cyclopropyl-6-(/V-(2-(7-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-/V-methylbenzofuran-3-carboxamide (45 mg, 0.077 mmol, 4%) as a white solid. ¹H NMR (300MHz, Chloroform-d₃) δ: 7.89 - 7.85 (m, 2 H), 7.50 - 7.44 (m, 3H), 7.22 - 7.17 (m, 2H), 7.05 - 6.94 (m, 2H), 5.77 (s, 1 H), 5.31 - 5.21 (m, 1 H), 4.02 - 3.85 (m, 2H), 3.05 (s, 3H), 2.99 (d, 3H), 2.37 - 2.28 (m, 2 H), 1 .77 - 1 .74 (m, 1 H), 1.07 - 0.94 (m, 3H) 0.71 (m, 1 H). LCMS(m/z, ES⁺)= 581 .1 (M+H).

Example 64

6-IT2-(6-Crtloro-1 -hydroxy-1 , 3-dihvdro-2,1 -benzoxaborol-3-yl)ethyll(methylsulfonyl)aminol-5- c clopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide

Step 1: 1-(2-Bromo-4-chlorophenyl)-2-propen-1-ol

A solution of 2-bromo-4-chlorobenzaldehyde (9.1 g, 41 .5 mmol) in tetrahydrofuran (200 ml.) was treated with 1.0M vinylmagnesium bromide (47.7 ml_, 47.7 mmol) and maintained with stirring at room temperature for 2 hours. The mixture was poured into 10% ammonium chloride (aq) and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 1 -(2-bromo-4-chlorophenyl)-2-propen-1-ol (9.31 g, 37.6 mmol, 91 % yield) as a clear oil. ¹H NMR (DMSO-d₆) δ: 7.70 (d, J = 2.0 Hz, 1 H), 7.45 - 7.55 (m, 2H), 5.80 - 5.96 (m, 2H), 5.32 (t, J = 4.9 Hz, 1 H), 5.24 (dt, J = 17.2, 1 .6 Hz, 1 H), 5.10 (dt, J = 10.3, 1.5 Hz, 1 H).

Step 2: {[1-(2-Bromo-4-chlorophenyl)-2-propen-1-yl]oxy}(1 , 1-dimethylethyl)dimethylsilane A solution of 1-(2-bromo-4-chlorophenyl)-2-propen-1-ol (9.31 g, 37.6 mmol) in N,N- dimethylformamide (100 ml.) was treated with imidazole (2.56 g, 37.6 mmol) and TBSCI (5.67 g, 37.6 mmol). The mixture was maintained with stirring at room temperature for 16 hours. The mixture was diluted with diethyl ether and washed three times with 5% LiCI (aq) and once with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford {[1-(2-bromo-4-chlorophenyl)-2-propen-1-yl]oxy}(1 , 1- dimethylethyl)dimethylsilane (9.61 g, 26.6 mmol, 70.6 % yield) as a clear oil. ¹H NMR (CHLOROFORM-d) δ: 7.48 - 7.54 (m, 2H), 7.31 (dd, J = 8.4, 2.0 Hz, 1 H), 5.89 (ddd, J = 17.0, 10.3, 5.0 Hz, 1 H), 5.51 (d, J = 5.1 Hz, 1 H), 5.31 - 5.39 (m, 1 H), 5.10 (dt, J = 10.2, 1 .5 Hz, 1 H), 0.92 (s, 9H), 0.10 (s, 3H), 0.01 (s, 3H). Step 3: 3-(2-Bromo-4-chlorophenyl)-3-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}-1 -propanol A solution of {[1-(2-bromo-4-chlorophenyl)-2-propen-1 -yl]oxy}(1 , 1- dimethylethyl)dimethylsilane (4.00 g, 1 1 .06 mmol) in THF (40 ml.) was cooled to 0°. A solution of 9-BBN (33.2 ml_, 0.5 M in THF) was added drop wise over 35 min. The reaction was allowed to warm to rt overnight. The reaction was cooled to 0° and treated with a solution of sodium hydroxide (18.4 ml_, 3.0 M), followed by 30% hydrogen peroxide (1 1.3 ml_). After 30 min, allowed to warm to rt. After another 30 min, the reaction mixture was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% dichloromethane in hexanes) afforded 3-(2-bromo-4- chlorophenyl)-3-{[(1 , 1-dimethylethyl)(dimethyl)silyl]oxy}-1 -propanol (4.30 g, quantitative yield) as a colorless oil. ¹H NMR (CHLOROFORM-d) δ: 7.49 - 7.56 (m, 2H), 7.33 (dd, J = 8.4, 2.0 Hz, 1 H), 5.25 (dd, J = 7.7, 3.6 Hz, 1 H), 3.71 - 3.81 (m, 2H), 1.93 - 2.09 (m, 1 H), 1.74 - 1.89 (m, 1 H), 0.91 (s, 9H), 0.09 (s, 3H), -0.12 (s, 3H). LCMS {m/z, ES⁺) = 379 (M+H). Step 4: {[3-Bromo-1-(2-bromo-4-chlorophenyl)propyl]oxy}(1, 1 -dimethylethyl)dimethylsilane A solution of 3-(2-bromo-4-chlorophenyl)-3-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}-1- propanol (2.88 g, 7.58 mmol) and triphenylphosphine (2.39 g, 9.10 mmol) in dichloromethane (40 ml.) was cooled to 0° and treated with NBS (1 .62 g, 9.10 mmol). The reaction was allowed to warm to room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was back-extracted with DCM. The combined organic layers were washed with water (1 x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (100% hexanes) afforded {[3-bromo-1-(2-bromo-4-chlorophenyl)propyl]oxy}(1 , 1 -dimethylethyl)dimethylsilane (2.46 g, 73%) as a colorless oil. ¹ H NMR (CHLOROFORM-d) δ: 7.52 (d, J = 2.1 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.31 (dd, J = 8.4, 2.0 Hz, 1 H), 5.18 (dd, J = 8.7, 3.1 Hz, 1 H), 3.37 - 3.63 (m, 2H), 1 .93 - 2.26 (m, 2H), 0.82 - 0.97 (m, 9H), 0.12 (s, 3H), -0.14 (s, 3H) .

Step 5: 6-[(3-(2-Bromo-4-chlorophenyl)-3-{[(1 , 1- dime thyle thy I) ( dime thy I) silyl]oxy}propyl) ( me thylsulfonyl)amino ]-5-cyclopropyl-2- ( 4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (1 .71 g, 4.25 mmol), {[3-bromo-1-(2-bromo-4- chlorophenyl)propyl]oxy}(1 , 1-dimethylethyl)dimethylsilane (2.45 g, 5.52 mmol) and potassium carbonate (1.47 g, 10.62 mmol) in acetonitrile (50 mL) was heated to 75° for 22 hours. To this was added DMF (10 mL) and heating was continued for another 24 hours. The temperature was increased to 85° for another 5 hours. The mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (1x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[(3-(2-bromo-4-chlorophenyl)-3-{[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (2.84 g, 87%) as a light yellow foam.

¹H NMR (DMSO-de) δ: 8.43 (br. s., 1 H), 7.94 (m, 2H), 7.74 - 7.86 (m, 1 H), 7.68 (d, J = 7.9 Hz, 1 H), 7.31 - 7.54 (m, 4H), 7.05 (s, 1 H), 4.85 - 5.05 (m, 1 H), 3.67 - 3.88 (m, 2H), 3.12 (s, 3H), 2.82 (br. s., 3H), 2.20 - 2.39 (m, 1 H), 1.68 - 1.93 (m, 2H), 0.85 - 1 .10 (m, 3H), 0.71 - 0.85 (m, 9H), 0.30 - 0.59 (m, 1 H), 0.01 (s, 3H), -0.19 (d, 3H). LCMS {m/z, ES⁺) = 763 (M+H).

Step 6: 6-[[3-(2-Bromo-4-chlorophenyl)-3-hydroxypropyl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[(3-(2-bromo-4-chlorophenyl)-3-{[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (2.83 g, 3.70 mmol) in THF (40 mL) was treated with 5N HCI (10 mL) and stirred at room temperature for 3.5 days. The reaction mixture was poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine (1x) then dried over sodium sulfate and concentrated.

Separately, a solution of 6-[(3-(2-bromo-4-chlorophenyl)-3-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (1.43 g, 1.87 mmol) in THF (20 mL) was treated with 1 N HCI (10 mL) and heated at 55° for 19 hours, then heated under reflux until reaction was judged to be mostly complete by LC/MS. The reaction mixture was poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine (1x) then dried over sodium sulfate and concentrated. Both of these crude products were purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to afford 6-[[3-(2-bromo-4-chlorophenyl)-3-hydroxypropyl](methylsulfonyl)amino]-5-cyclopropyl- 2-(4-fluorophenyl)-/V-methyl-1 -benzofuran-3-carboxamide (3.47 g, 96% combined yield) as a pale yellow foam. ¹H NMR (DMSO-d₆) δ: 8.45 (m, 1 H), 7.90 - 8.00 (m, 2H), 7.83 (d, J = 16.8 Hz, 1 H), 7.64 (t, J = 1 .9 Hz, 1 H), 7.43 - 7.55 (m, 2H), 7.39 (td, J = 8.9, 1.6 Hz, 2H), 7.05 (d, J = 4.4 Hz, 1 H), 5.66 (dd, J = 13.4, 4.5 Hz, 1 H), 4.70 - 4.85 (m, 1 H), 3.76 - 3.92 (m, 2H), 3.14 (d, J = 1 .7 Hz, 3H), 2.83 (d, J = 4.6 Hz, 3H), 2.23 - 2.38 (m, 1 H), 1 .52 - 1 .96 (m, 2H), 0.79 - 1.03 (m, 3H), 0.39 - 0.60 (m, 1 H). LCMS {m/z, ES⁺) = 649 (M+H).

Step 7: 6-[(3-(2-Bromo-4-chlorophenyl)-3- {[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluoroph

methyl-1-benzofuran-3-carboxamide

A solution of 6-[[3-(2-bromo-4-chlorophenyl)-3-hydroxypropyl](methylsulfonyl)amino]- 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (1 .75 g, 2.69 mmol) in THF (30 ml.) was treated with DIEA (0.94 ml_, 5.38 mmol) and chloromethyl methyl ether (0.41 ml_, 5.38 mmol). The reaction was heated in a 50° bath for 16 hours, then cooled to room temperature. Separately, a solution of 6-[[3-(2-bromo-4-chlorophenyl)-3- hydroxypropyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1- benzofuran-3-carboxamide (500 mg, 0.769 mmol) in THF (10 ml.) was treated with DIEA (0.27 ml_, 1 .54 mmol) and chloromethyl methyl ether (0.12 ml_, 1 .54 mmol). The reaction was heated in a 50° bath for 21 hours, then cooled to room temperature. The two reaction mixtures were combined, diluted with water, and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and

concentrated. Purification by silica gel chromatography (0 to 75% ethyl acetate in hexanes) afforded 6-[(3-(2-bromo-4-chlorophenyl)-3- {[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (1.74 g, 72% for both reactions) as a white foam. ¹ H NMR (DMSO-d₆) δ: 8.44 (m, 1 H), 7.94 (ddd, J = 8.8, 5.4, 1.4 Hz, 2H), 7.84 (d, J = 6.7 Hz, 1 H), 7.70 (dd, J = 4.8, 2.0 Hz, 1 H), 7.33 - 7.52 (m, 4H), 7.05 (d, J = 4.7 Hz, 1 H), 4.86 (ddd, J = 12.9, 8.5, 4.0 Hz, 1 H), 4.53 (dd, J = 6.8, 2.2 Hz, 1 H), 4.37 (dd, J = 6.8, 4.1 Hz, 1 H), 3.68 - 3.94 (m, 2H), 3.05 - 3.26 (m, 6H), 2.82 (d, J = 4.6 Hz, 3H), 2.22 - 2.40 (m, 1 H), 1.72 - 1.95 (m, 2H), 0.78 - 1 .05 (m, 3H), 0.36 - 0.62 (m, 1 H). LCMS {m/z, ES⁺) = 693 (M+H).

Step 8: 6-[[2-(6-C loro-1- ydroxy-1 ,3-di ydro-2, 1-benzoxaborol-3- yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-ben

carboxamide

A mixture of 6-[(3-(2-bromo-4-chlorophenyl)-3- {[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (500 m g, 0.72 mmol), potassium acetate (141 mg, 1 .44 mmol), bis(pinacolato)diboron (274 mg, 1.08 mmol), sodium bromide (74 mg, 0.72 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (59 mg, 0.072 mmol) in 1 ,4-dioxane (15 ml.) in a thick-walled glass pressure vessel was degassed, then heated at 90°C with stirring for 16 hours.

Additional bis(pinacolato)diboron (91 mg, 0.36 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (29 mg, 0.036 mmol) were added and the reaction was heated for another 24 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[(3- [4-chloro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-3- {[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (0.58 g, 81 % pure by LC/MS) as a colorless oil.

This residue was dissolved in THF (15 ml.) and treated with 1 N HCI (5 ml_), then heated under reflux. After 16 hours, the reaction was treated with 5N HCI (1 ml_), and heating was continued for 4 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization afforded 6-[[2-(6-chloro-1-hydroxy- 1 ,3-dihydro-2, 1-benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (0.23 g, 43% over 2 steps) as a fluffy white solid. ¹ H NMR (METHANOL-d₄) δ: 7.86 - 7.96 (m, 2H), 7.70 (d, J = 16.8 Hz, 1 H), 7.54 (d, J = 1 .7 Hz, 1 H), 7.39 (ddd, J = 8.1 , 6.2, 2.0 Hz, 1 H), 7.12 - 7.29 (m, 4H), 5.17 - 5.37 (m, 1 H), 3.70 - 4.17 (m, 2H), 3.05 - 3.17 (m, 3H), 2.94 (s, 3H), 2.15 - 2.52 (m, 2H), 1.56 - 1.86 (m, 1 H), 0.84 - 1 .14 (m, 3H), 0.46 - 0.76 (m, 1 H). LCMS {m/z, ES⁺) = 597 (M+H).

Example 65

6-rr2-(5-Chloro-1-hvdroxy-1 ,3-dihvdro-2,1 -benzoxaborol-3-yl)ethyll(methylsulfonyl)aminol-5- cvclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide

Step 1: 1-(2-Bromo-5-chlorophenyl)-2-propen-1-ol

A solution of 2-bromo-5-chlorobenzaldehyde (8 g, 36.5 mmol) in tetrahydrofuran (200 ml.) maintained at 0°C was treated with 1.0M vinylmagnesium bromide in THF (41 .9 ml_, 41 .9 mmol) and maintained with stirring at room temperature for 3 hours. The mixture was poured into saturated ammonium chloride (aq) and the organic layer was diluted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 1 -(2-bromo-5- chlorophenyl)-2-propen-1 -ol (4.99 g, 20.16 mmol, 55.3 % yield) as a clear oil. ¹H NMR (DMSO-d₆) δ: 7.61 (d, J = 8.6 Hz, 1 H), 7.50 (d, J = 2.7 Hz, 1 H), 7.29 (dd, J = 8.5, 2.6 Hz, 1 H), 5.83 - 5.99 (m, 2H), 5.20 - 5.36 (m, 2H), 5.12 (dt, J = 10.3, 1 .5 Hz, 1 H).

Step 2: {[1-(2-Bromo-5-chlorophenyl)-2-propen-1-yl]oxy}(1, 1-dimethylethyl)dimethylsilane A solution of 1-(2-bromo-5-chlorophenyl)-2-propen-1 -ol (5 g, 20.20 mmol), imidazole

(2.75 g, 40.4 mmol), and TBSCI (3.35 g, 22.22 mmol) in N,N-dimethylformamide (50 mL) was maintained with stirring at room temperature for 16 hours. The mixture was poured into diethyl ether and washed three times with 5% LiCI (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford {[1 -(2-bromo-5-chlorophenyl)-2-propen-1-yl]oxy}(1 , 1- dimethylethyl)dimethylsilane (6.23 g, 17.22 mmol, 85 % yield) as a clear oil. ¹H NMR

(CHLOROFORM-d) δ: 7.53 (d, J = 2.5 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.09 (dd, J = 8.5, 2.6 Hz, 1 H), 5.89 (ddd, J = 17.0, 10.3, 4.9 Hz, 1 H), 5.49 (d, J = 4.9 Hz, 1 H), 5.37 (d, J = 17.0 Hz, 1 H), 5.1 1 (d, J = 10.3 Hz, 1 H), 0.85 - 0.99 (m, 9H), 0.10 (s, 3H), (0.01 (s, 3H).

Step 3: 3-(2-Bromo-5-chlorophenyl)-3-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}-1 -propanol

A solution of {[1-(2-bromo-5-chlorophenyl)-2-propen-1 -yl]oxy}(1 , 1- dimethylethyl)dimethylsilane (3.00 g, 8.29 mmol) in THF (30 mL) was cooled to 0°. A solution of 9-BBN (24.9 mL, 0.5 M in THF) was added drop wise over 25 min. The reaction was allowed to warm to rt overnight. The reaction was cooled to 0° and treated with a solution of sodium hydroxide (13.8 mL, 3.0 M), followed by 30% hydrogen peroxide (8.5 mL). After stirring for 1.5 h, the reaction mixture was diluted with water and allowed to warm to room temperature and then extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 20% ethyl acetate in hexanes) afforded 3-(2-bromo-5-chlorophenyl)-3- {[(1 ,1 -dimethylethyl)(dimethyl)silyl]oxy}-1 -propanol (2.97 g, 94% yield) as a colorless oil. ¹H NMR (CHLOROFORM-d) δ: 7.56 (d, J = 2.6 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.1 1 (dd, J = 8.5, 2.6 Hz, 1 H), 5.22 (dd, J = 7.9, 3.5 Hz, 1 H), 3.66 - 3.89 (m, 2H), 1 .72 - 2.16 (m, 3H), 0.86 - 0.96 (m, 9H), 0.04 - 0.15 (m, 3H), -0.16 - -0.06 (m, 3H). LCMS {m/z, ES⁺) = 379 (M+H).

Step 4: {[3-bromo-1-(2-bromo-5-chlorophenyl)propyl]oxy}(1, 1 -dimethylethyl)dimethylsilane

A solution of 3-(2-bromo-5-chlorophenyl)-3-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}-1- propanol (2.94 g, 7.74 mmol) and triphenylphosphine (2.44 g, 9.49 mmol) in dichloromethane (40 mL) was cooled to 0° and treated with NBS (1 .65 g, 9.29 mmol). After 1 hour, the reaction was allowed to warm to room temperature. After another 3 hours, the reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was back-extracted with DCM. The combined organic layers were washed with water (1 x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (100% hexanes) afforded {[3-bromo-1-(2-bromo-5- chlorophenyl)propyl]oxy}(1 , 1-dimethylethyl)dimethylsilane (2.89 g, 84%) as a colorless oil. ¹H NMR (CHLOROFORM-d) δ: 7.52 (d, J = 2.6 Hz, 1 H), 7.43 (d, J = 8.5 Hz, 1 H), 7.1 1 (dd, J = 8.5, 2.6 Hz, 1 H), 5.16 (dd, J = 8.8, 2.9 Hz, 1 H), 3.38 - 3.65 (m, 2H), 1.95 - 2.29 (m, 2H), 0.87 - 0.94 (m, 9H), 0.03 - 0.20 (m, 3H), -0.19 - -0.06 (m, 3H).

Step 5: 6-[(3-(2-Bromo-5-chlorophenyl)-3-{[(1 , 1- dime thyle thy I) ( dime thy I) silyl]oxy}propyl) ( me thylsulfonyl)amino ]-5-cyclopropyl-2- ( 4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (2.00 g, 4.97 mmol), {[3-bromo-1-(2-bromo-5- chlorophenyl)propyl]oxy}(1 , 1-dimethylethyl)dimethylsilane (2.86 g, 6.46 mmol) and potassium carbonate (1.72 g, 12.42 mmol) in acetonitrile (50 mL) was heated to 75° for 16 hours. To this was added DMF (10 mL) and heating was continued for another 24 hours. The mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (1 x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[(3-(2-bromo-5-chlorophenyl)-3-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (3.67 g, 97%) as a pale yellow foam. ¹H NMR (DMSO-de) δ: 8.43 (m, 1 H), 7.94 (m, 2H), 7.74 - 7.87 (m, 1 H), 7.56 (dd, J = 10.3, 8.5 Hz, 1 H), 7.33 - 7.46 (m, 3H), 7.27 (m, 1 H), 7.05 (s, 1 H), 4.84 - 5.02 (m, 1 H), 3.67 - 3.91 (m, 2H), 3.13 (d, J = 4.2 Hz, 3H), 2.82 (d, J = 4.6 Hz, 3H), 2.17 - 2.40 (m, 1 H), 1 .71 - 1 .94 (m, 2H), 0.86 - 1 .06 (m, 3H), 0.69 - 0.86 (m, 9H), 0.33 - 0.61 (m, 1 H), 0.01 (d, J = 4.4 Hz, 3H), - 0.18 (d, J = 5.2 Hz, 3H). LCMS {m/z, ES⁺) = 763 (M+H).

Step 6: 6-[[3-(2-Bromo-5-chlorophenyl)-3-hydroxypropyl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[(3-(2-bromo-5-chlorophenyl)-3-{[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (3.65 g, 4.78 mmol) in THF (50 mL was treated with 5N HCI (15 mL) and stirred at room temperature for 16 hours, then heated at 50° for 5 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with 10% aqueous sodium carbonate (1x) and brine (1 x), then dried over sodium sulfate and concentrated. The resulting sticky yellow foam was triturated in a mixture of dichloromethane and hexanes to afford 6-[[3-(2-bromo-5-chlorophenyl)-3- hydroxypropyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1- benzofuran-3-carboxamide (2.81 g, 91 %) as an off-white solid. ¹H NMR (DMSO-d₆) δ: 8.44 (m, 1 H), 7.94 (dd, J = 7.7, 5.5 Hz, 2H), 7.83 (d, J = 14.1 Hz, 1 H), 7.51 (ddd, J = 19.2, 8.1 , 2.2 Hz, 2H), 7.39 (td, J = 8.9, 1.3 Hz, 2H), 7.19 - 7.29 (m, 1 H), 7.05 (d, J = 4.4 Hz, 1 H), 5.60 - 5.85 (m, 1 H), 4.75 (m, 1 H), 3.74 - 3.93 (m, 2H), 3.15 (s, 3H), 2.82 (m, 3H), 2.20 - 2.39 (m, 1 H), 1 .50 - 1 .99 (m, 2H), 0.76 - 1 .06 (m, 3H), 0.39 - 0.63 (m, 1 H). LCMS {m/z, ES⁺) = 649 (M+H). Step 7: 6-[(3-(2-Bromo-5-chlorophenyl)-3-

{[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorop

methyl-1-benzofuran-3-carboxamide

A solution of 6-[[3-(2-bromo-5-chlorophenyl)-3-hydroxypropyl](methylsulfonyl)amino]- 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (2.81 g, 4.32 mmol) in THF (35 mL) was treated with DIEA (1.28 mL, 7.35 mmol) and chloromethyl methyl ether (0.56 mL,7.35 mmol). The reaction was heated in a 50° bath for 16 hours, at which time additional DIEA (1.28 mL, 7.35 mmol) and chloromethyl methyl ether (0.56 mL,7.35 mmol) were added. The bath temperature was increased to 55° for 24 hours. The reaction was cooled to room temperature and diluted with water, then extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 75% ethyl acetate in hexanes) afforded 6-[(3-(2-bromo-5-chlorophenyl)-3-

{[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (2.15 g, 72%) as a white solid. ¹H NMR (DMSO-d₆) δ: 8.44 (m, 1 H), 7.94 (m, 2H), 7.84 (d, J = 5.1 Hz, 1 H), 7.58 (dd, J = 8.5, 6.2 Hz, 1 H), 7.34 - 7.44 (m, 3H), 7.29 (ddd, J = 8.5, 4.7, 2.7 Hz, 1 H), 7.05 (d, J = 4.7 Hz, 1 H), 4.77 - 4.93 (m, 1 H), 4.56 (dd, J = 6.9, 2.5 Hz, 1 H), 4.35 - 4.47 (m, 1 H), 3.73 - 3.94 (m, 2H), 3.18 - 3.25 (m, 3H), 3.07 - 3.18 (m, 3H), 2.82 (m, 3H), 2.22 - 2.42 (m, 1 H), 1.80 - 1.96 (m, 2H), 0.81 - 1.05 (m, 3H), 0.38 - 0.63 (m, 1 H). LCMS {m/z, ES⁺) = 693 (M+H).

Step 8: 6-[[2-(5-Chloro-1-hydroxy-1,3-dihydro-2, 1-benzoxaborol-3- yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyi ^

carboxamide

A mixture of 6-[(3-(2-bromo-5-chlorophenyl)-3- {[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (1.15 g, 1.66 mmol), potassium acetate (0.33 g, 3.31 mmol), bis(pinacolato)diboron (0.63 g, 2.49 mmol), sodium bromide (170 mg, 1 .66 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (135 mg, 0.166 mmol) in 1 ,4-dioxane (20 mL) in a thick-walled glass pressure vessel was degassed, then heated at 85 °C with stirring for 64 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[(3-[5-chloro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-3-

{[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (1.22 g, 56% pure by LC/MS) as a light green oil.

This residue was dissolved in THF (30 mL) and treated with 1 N HCI (10 mL), then heated under reflux. After 16 hours, the reaction was treated with 5N HCI (1 mL), and heating was continued for 4 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization afforded 6-[[2-(5-chloro-1-hydroxy- 1 ,3-dihydro-2, 1-benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (0.35 g, 35% over 2 steps) as a fluffy white solid. ¹ H NMR (METHANOL-d₄) δ: 7.86 - 7.97 (m, 2H), 7.70 (m, 1 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.20 - 7.35 (m, 4H), 7.16 (s, 1 H), 5.15 - 5.37 (m, 1 H), 3.69 - 4.19 (m, 2H), 3.03 - 3.17 (m, 3H), 2.87 - 3.01 (m, 3H), 2.15 - 2.54 (m, 2H), 1 .53 - 1 .87 (m, 1 H), 0.82 - 1 .13 (m, 3H), 0.46 - 0.75 (m, 1 H). LCMS {m/z, ES⁺) = 597 (M+H).

Example 66

6-rr2-(4-Chloro-1-hvdroxy-1 ,3-dihvdro-2,1 -benzoxaborol-3-yl)ethyll(methylsulfonyl)aminol-5- cvclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide

Step 1: 1-(2-bromo-6-chlorophenyl)-2-propen-1-ol

A solution of 2-bromo-6-chlorobenzaldehyde (7 g, 31.9 mmol) (synthesis described Organic Process Research and Development (2008) 12, p. 1293.) in tetrahydrofuran (150 mL) was cooled to 0°C and treated drop wise with 1.0M vinyl magnesium chloride in THF (39.9 mL, 39.9 mmol). The mixture was maintained with stirring for 2 hours and then quenched via slow addition of 10% ammonium chloride (aq). The mixture was diluted with ethyl acetate and the organic layer was washed with water, separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 1-(2-bromo-6-chlorophenyl)-2-propen-1 -ol (6.1 1 g, 24.69 mmol, 77 % yield) as a clear oil. ¹H NMR (DMSO-d₆) δ: 7.60 (dd, J = 8.0, 1 .2 Hz, 1 H), 7.45 (dd, J = 8.0, 1 .0 Hz, 1 H), 7.21 (t, J = 8.1 Hz, 1 H), 6.18 (ddd, J = 17.3, 10.4, 5.1 Hz, 1 H), 5.80 - 5.87 (m, 1 H), 5.73 (d, J = 4.7 Hz, 1 H), 5.09 - 5.22 (m, 2H).

Step 2: {[1-(2-bromo-6-chlorophenyl)-2-propen-1-yl]oxy}(1, 1-dimethylethyl)dimethylsilane

A solution of 1-(2-bromo-6-chlorophenyl)-2-propen-1 -ol (6.1 1 g, 24.69 mmol) in N,N- dimethylformamide (100 mL) was treated sequentially with imidazole (4.20 g, 61 .7 mmol) followed by TBSCI (4.84 g, 32.1 mmol) and maintained with stirring at room temperature for 16 hours. The mixture was poured into diethyl ether and washed three times with 5% LiCI (aq) and once with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford {[1 -(2-bromo-6-chlorophenyl)-2-propen-1-yl]oxy}(1 , 1- dimethylethyl)dimethylsilane (7.98 g, 22.06 mmol, 89 % yield) as a clear oil. ¹H NMR

(DMSO-d₆) δ: 7.63 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.23 (t, J = 8.1 Hz, 1 H), 6.15 (ddd, J = 17.1 , 10.4, 5.1 Hz, 1 H), 5.93 (d, J = 4.9 Hz, 1 H), 5.29 (dt, J = 17.0, 1.5 Hz, 1 H), 5.19 (dt, J = 10.3, 1.6 Hz, 1 H), 0.86 (s, 9H), 0.06 (s, 3H), -0.12 (s, 3H). Step 3: 3-(2-Bromo-6-chlorophenyl)-3-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}-1-propanol A solution of {[1-(2-bromo-6-chlorophenyl)-2-propen-1 -yl]oxy}(1 , 1- dimethylethyl)dimethylsilane (4.00 g, 1 1 .06 mmol) in THF (40 mL) was cooled to 0°. A solution of 9-BBN (33.5 mL, 0.5 M in THF) was added drop wise over 35 min. The reaction was allowed to warm to rt overnight. The reaction was cooled to 0° and treated with a solution of sodium hydroxide (18.4 mL, 3.0 M), followed by 30% hydrogen peroxide (1 1.3 mL). After stirring for 1 .5 h, the reaction mixture was diluted with water and allowed to warm to rt, then extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 25% ethyl acetate in hexanes) afforded 3-(2-bromo-6-chlorophenyl)-3-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}-1-propanol (4.02 g, 96% yield) as a colorless oil. ¹H NMR (CHLOROFORM-d) δ: 7.42 - 7.56 (m, 1 H), 7.29 - 7.38 (m, 1 H), 7.04 (t, 1 H), 5.55 - 5.78 (m, 1 H), 3.73 - 3.94 (m, 2H), 2.39 - 2.71 (m, 1 H), 2.16 (br. s., 1 H), 1.73 - 1.97 (m, 1 H), 0.91 and 0.90 (s, 9H, rotamers), 0.09 and 0.08 (s, 3H, rotamers), -0.19 and -0.20 (s, 3H, rotamers). LCMS {m/z, ES⁺) = 379 (M+H).

Step 4: {[3-Bromo-1-(2-bromo-6-chlorophenyl)propyl]oxy}(1, 1 -dimethylethyl)dimethylsilane A solution of 3-(2-bromo-6-chlorophenyl)-3-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}-1- propanol (4.00 g, 10.53 mmol) and triphenylphosphine (3.31 g, 12.64 mmol) in

dichloromethane (50 mL) was cooled to 0° and treated with NBS (2.25 g, 12.64 mmol). After 30 min, the reaction was allowed to warm to rt. After an additional 1 h, the reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was back- extracted with DCM. The combined organic layers were washed with water (1 x) and brine (1 x), then dried over sodium sulfate and concentrated. Purification by silica gel

chromatography (100% hexanes) afforded {[3-bromo-1-(2-bromo-6- chlorophenyl)propyl]oxy}(1 , 1-dimethylethyl)dimethylsilane (4.23 g, 91 %) as a colorless oil. ¹H NMR (DMSO-de, 85 °) δ: 7.62 (dd, 1 H), 7.47 (d, 1 H), 7.23 (t, 1 H), 5.47 - 5.76 (m, 1 H), 3.47 - 3.76 (m, 2H), 2.66 - 2.93 (m, 1 H), 2.00 - 2.18 (m, 1 H), 0.87 (s, 9H), 0.1 1 (s, 3H), -0.17 (s, 3H).

Step 5: 6-[(3-(2-Bromo-6-chlorophenyl)-3-{[(1 , 1- dime thyle thy I) ( dime thy I) silyl]oxy}propyl) ( me thylsulfonyl)amino ]-5-cyclopropyl-2- ( 4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (2.95 g, 7.33 mmol), {[3-bromo-1-(2-bromo-6- chlorophenyl)propyl]oxy}(1 , 1-dimethylethyl)dimethylsilane (4.22 g, 9.53 mmol) and potassium carbonate (2.53 g, 18.33 mmol) in 5:1 acetonitrile/DMF (90 mL) was heated to 75° for 16 h. The temperature was increased to 85° for 6 h. The mixture was cooled to rt, poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (1 x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[(3-(2-bromo-6- chlorophenyl)-3-{[(1 , 1-dimethylethyl)(dimethyl)silyl]oxy}propyl)(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (5.08 g, 91 %) as a yellow foam. ¹ H NMR (DMSO-d₆) δ: 8.38 - 8.50 (m, 1 H), 7.94 (m, 2H), 7.80 - 7.89 (m, 1 H), 7.53 - 7.66 (m, 1 H), 7.32 - 7.52 (m, 3H), 7.13 - 7.27 (m, 1 H), 7.06 (s, 1 H), 5.21 - 5.55 (m, 1 H), 3.81 - 3.98 (m, 1 H), 3.56 - 3.78 (m, 1 H), 3.04 - 3.20 (m, 3H), 2.74 - 2.89 (m, 3H), 2.23 - 2.54 (m, 2H), 1 .56 - 1 .95 (m, 1 H), 0.86 - 1 .06 (m, 3H), 0.66 - 0.86 (m, 9H), 0.35 - 0.59 (m, 1 H), -0.06 - 0.1 1 (m, 3H), -0.38 - -0.20 (m, 3H). LCMS {m/z, ES⁺) = 763 (M+H).

Step 6: 6-[[3-(2-Bromo-6-chlorophenyl)-3-hydroxypropyl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[(3-(2-bromo-6-chlorophenyl)-3-{[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (5.06 g, 6.62 mmol) in THF (70 treated with 5N HCI (20 mL) and stirred at rt for 16 h, then heated under reflux for 7 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and washed with water (1 x), 10% aqueous sodium carbonate (1 x), and brine (1 x), then dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to afford 6-[[3-(2-bromo-6-chlorophenyl)-3- hydroxypropyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1- benzofuran-3-carboxamide (4.13 g, 96%) as an off-white foam. ¹H NMR (DMSO-d₆) δ: 8.39 - 8.52 (m, 1 H), 7.95 (dd, 2H), 7.85 (d, 1 H), 7.56 (td, 1 H), 7.32 - 7.46 (m, 3H), 7.16 (td, 1 H), 7.06 (d, 1 H), 5.47 - 5.70 (m, 1 H), 5.13 - 5.38 (m, 1 H), 3.77 - 3.99 (m, 1 H), 3.57 - 3.77 (m, 1 H), 3.06 - 3.22 (m, 3H), 2.82 (m, 3H), 2.18 - 2.44 (m, 2H), 1.58 - 1.95 (m, 1 H), 0.77 - 1.08 (m, 3H), 0.37 - 0.63 (m, 1 H). LCMS {m/z, ES⁺) = 649 (M+H).

Step 7: 6-[(3-(2-Bromo-6-chlorophenyl)-3-

methyl-1-benzofuran-3-carboxamide

A solution of 6-[[3-(2-bromo-6-chlorophenyl)-3-hydroxypropyl](methylsulfonyl)amino]- 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (4.13 g, 6.35 mmol) in THF (60 mL) was treated with DIEA (1.89 mL, 10.8 mmol) and chloromethyl methyl ether (0.82 mL, 10.8 mmol). The reaction was heated to an internal temperature of 45° for 16 h, at which time additional DIEA (1.89 mL, 10.8 mmol) and chloromethyl methyl ether (0.82 mL, 10.8 mmol) were added. The temperature was increased to 53° for 24 h. The reaction was cooled to room temperature and diluted with water, then extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 75% ethyl acetate in hexanes) afforded 6-[(3-(2-bromo-6-chlorophenyl)-3-

{[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (3.30 g, 75%) as a white foam. ¹H NMR (DMSO-d₆) δ: 8.44 (m, 1 H), 7.95 (m, 2H), 7.87 (d, 1 H), 7.55 - 7.65 (m, 1 H), 7.33 - 7.51 (m, 3H), 7.21 (m, 1 H), 7.05 (d, 1 H), 5.15 - 5.41 (m, 1 H), 4.54 (t, J = 6.8 Hz, 1 H), 4.35 (d, J = 6.8 Hz, 1 H), 3.59 - 3.99 (m, 2H), 3.06 - 3.20 (m, 6H), 2.82 (m, 3H), 2.42 - 2.58 (m, 1 H), 2.27 - 2.41 (m, 1 H), 1 .73 - 1.97 (m, 1 H), 0.79 - 1.06 (m, 3H), 0.41 - 0.58 (m, 1 H). LCMS {m/z, ES⁺) = 693 (M+H).

Step 8: 6-[[2-(4-Chloro-1-hydroxy-1,3-dihydro-2, 1-benzoxaborol-3- yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-ben

carboxamide.

A mixture of 6-[(3-(2-bromo-6-chlorophenyl)-3- {[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (1.57 g, 2.26 mmol), potassium acetate (0.44 g, 4.52 mmol), bis(pinacolato)diboron (0.86 g, 3.39 mmol), sodium bromide (233 mg, 2.26 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (185 mg, 0.226 mmol) in 1 ,4-dioxane (20 ml.) in a thick-walled glass pressure vessel was degassed, then heated at 85 °C with stirring for 64 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[(3-[2-chloro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-3- {[(methyloxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (1.38 g, 76% pure by LC/MS) as a light green foam. This residue was dissolved in THF (30 ml.) and treated with 1 N HCI (10 ml_), then heated under reflux for 16 h. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (2x) and brine (1 x), then dried over sodium sulfate and concentrated. Purification by silica gel

chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization afforded 6-[[2-(4-chloro-1-hydroxy-1 ,3-dihydro- 2, 1 -benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (0.67 g, 50% over 2 steps) as a fluffy tan solid. ¹H NMR (METHANOL-d₄) δ: 7.91 (m, 2H), 7.62 - 7.78 (m, 1 H), 7.54 (m, 1 H), 7.28 - 7.41 (m, 2H), 7.24 (t, 2H), 7.15 (d, 1 H), 5.23 - 5.44 (m, 1 H), 3.68 - 4.14 (m, 2H), 3.02 - 3.22 (m, 3H), 2.87 - 3.02 (m, 3H), 2.56 - 2.79 (m, 1 H), 2.26 - 2.54 (m, 1 H), 1.61 - 1 .83 (m, 1 H), 0.81 - 1.15 (m, 3H), 0.44 - 0.74 (m, 1 H). LCMS {m/z, ES⁺) = 597 (M+H).

Example 67

5-Cvclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1-hvdroxy-3,4-dihvdro-1 H-benzorciri ,2loxaborinin- -yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide

Step 1: methyl 2-(2-bromophenyl)acetate

To a solution of 2-(2-bromophenyl)acetic acid (20.0 g, 0.09 mol, BeiJingOuHe) in MeOH (100 ml.) was added H₂S0₄ (2 ml.) and heated under reflux overnight. The reaction solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 ml.) and the organic solution washed with brine (2 x 100 ml_), dried over anhydrous Na₂S0₄. Removal of solvent under reduced pressure afforded methyl 2-(2- bromophenyl)acetate (21.0 g, 0.09 mol, 98.0 % yield) as a colorless oil.

Step 2: 2-(2-bromophenyl)ethanol

To a solution of LiAIH4 (1.0 g, 26 mmol) in THF (80 ml.) was added methyl 2-(2- bromophenyl)acetate (5.0 g, 22 mmol) in THF drop wise at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 min and then EtOAc (100 ml.) and water (20 ml.) were added. The solid was filtered off and the filtrate was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified by column chromatography to afford 2-(2- bromophenyl)ethanol (3.7 g, 18.4 mmol, 84 % yield) as a colorless oil. LC-MS (m/z, ES⁺)= 202 (M+H)

Step 3: 2-(2-bromophenyl)acetaldehyde

To a suspension of PCC (5.9 g, 28 mmol) in DCM (15 mL) was added a solution of 2- (2-bromophenyl)ethanol (3.7 g , 18 mmol) in DCM (20ml_) at room temperature whereupon a slightly exothermic reaction took place with the formation of a black reaction mixture which was kept stirring at room temperature for 15 hours. Then, ethyl ether (150 mL) was added and the mixture was filtered through silica gel on a pad of celite. The residue was washed with ether (50ml_) and the filtrate was concentrated under reduced pressure to afford crude product 2-(2-bromophenyl)acetaldehyde (3.4 g, 17 mmol, 94 % yield) as a light black oil. LCMS (m/z, ES 199 (M+H)

Step 4: 1-(2-bromop enyl)but-3-en-2-ol

To a solution of 2-(2-bromophenyl)acetaldehyde (3.4 g, 17 mmol) in 100 mL of THF was added vinyl-MgBr (19 mL, 19 mmol) drop wise at -60 °C under nitrogen atmosphere.

The resulting reaction mixture was stirred at room temperature for another hour. Ammonium chloride (saturated aq., 50 mL) was added and the organic layer was separated. The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 1-(2-bromophenyl)but-3-en-2- ol (2.8 g, 12 mmol, 74 % yield) as a colorless oil. LCMS (m/z, ES⁺)= 227 (M+H)

Step 5: (1-(2-bromophenyl)but-3-en-2-yloxy)(tert-butyl)dimethylsilane

To a solution of 1-(2-bromophenyl)but-3-en-2-ol (2.3 g, 10 mmol) in DMF (30mL) were added imidazole (1.7 g, 25 mmol) and TBSCI (2.3 g, 15 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. Water (50 ml) was added and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford (1 -(2-bromophenyl)but-3-en-2- yloxy)(ferf-butyl)dimethylsilane (2.9 g, 8.5 mmol, 85 % yield) as a colorless oil. LCMS (m/z, ES⁺)= 341 (M+H)

Step 6: 4-(2-bromophenyl)-3-(tert-butyldimethylsilyloxy)butan-1-ol

A solution of (1-(2-bromophenyl)but-3-en-2-yloxy)(ferf-butyl)dimethylsilane (2.9 g, 8.5 mmol) in THF (30mL) was added 9-BBN (0.5 M in THF, 26 mL, 13 mmol) under nitrogen atmosphere and stirred at room temperature overnight. The reaction mixture was cooled to 0 °C and NaOH (2N aq.15 mL) was added. After stirring for 1 hour, hydrogen peroxide (15 mL) was added and the resulting reaction mixture was stirred for 2 hours at room temperature. The separated organic layer was washed with brine (100 mL) and dried over anhydrous Na₂S0_4. After the removal of solvent, the residue was purified by column chromatography (eluting with PE to 10 % EA in PE) to afford 4-(2-bromophenyl)-3-(tert- butyldimethylsilyloxy)butan-1-ol (1.6 g, 4.5 mmol, 53 % yield) as a colorless oil. LCMS (m/z, ES+)= 359 (M+H).

Step 7: (4-bromo-1-(2-bromophenyl)butan-2-yloxy)(tert-butyl)dimethylsilane

A solution of 4-(2-bromophenyl)-3-(tert-butyldimethylsilyloxy)butan-1-ol (1 .6 g, 4.5 mmol), PPh₃ (1.8 g, 6.7 mmol) and NBS (1.2 g, 6.7 mmol) in DCM (100 mL) was stirred at room temperature for 1 hours. The reaction solution was concentrated under reduced pressure and the residue was purified with column chromatography to afford (4-bromo-1-(2- bromophenyl)butan-2-yloxy)(tert-butyl)dimethylsilane (1.72 g, 4.0 mmol, 91 % yield) as a colorless oil.

Step 8: 6-(N-(4-(2-bromophenyl)-3-(tert-butyldimethylsilyloxy)butyl)methylsu

cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (1.0 g, 2.5 mmol), (4-bromo-1 -(2-bromophenyl)butan-2- yloxy)(tert-butyl)dimethylsilane (1 .7 g, 4.0 mmol), potassium carbonate (1 .0 g, 7.5 mmol) and potassium iodide (400 mg, 2.5 mmol) in DMF (50 mL) was heated at 120 °C for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-(2-bromophenyl)-3- (tert-butyldimethylsilyloxy)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .2 g, 1 .6 mmol, 63 % yield) as a white solid. LCMS (m/z, ES 742 (M+H). Step 9: 6-(N-(3-(tert-butyldimethylsilyloxy)-4-(2-(4,4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2- yl)phenyl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbe

carboxamide

A solution of 6-(N-(4-(2-bromophenyl)-3-(tert- butyldimethylsilyloxy)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1.2 g, 1 .6 mmol), potassium carbonate (221 mg, 1.6 mmol), bis(pinacolato)diboron (4.1 g, 1.6 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (58 mg, 0.08 mmol) in 1 ,4-dioxane (100 ml.) was degassed and refilled with nitrogen three times and heated at 100 °C overnight. After the reaction mixture was cooled to room temperature, water (100 ml.) was added and the solution was extracted with EtOAc (3 x 80 ml_). The combined organic layers were dried over anhydrous Na₂S0_4. After the removal of solvent, The residue was purified with column chromatography to afford 6-(N-(3-(tert- butyldimethylsilyloxy)-4-(2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (710 mg, 0.90 mmol, 55% yield) as a white solid. LCMS (m/z, ES⁺) = 791 (M+H)

Step 10: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(1-hydroxy-3,4-dihydro-1H- benzo[c][1,2]oxaborinin-3-yl)ethyl)methylsulfonamido)-N-methylbenzo

A solution of 6-(N-(3-(tert-butyldimethylsilyloxy)-4-(2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)butyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (700 mg, crude, 0.90 mmol) and HCI (5N aq., 10 ml.) in THF (60 ml.) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(1-hydroxy-3,4-dihydro-1 H- benzo[c][1 ,2]oxaborinin-3-yl)ethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (260 mg, 51 % yield) as a white solid. ¹H NMR (METHANOL-d4) δ: 7.94 (q, 2H), 7.89 (d, 1 H), 7.58 (d,1 H), 7.35 (m, 6H), 4.36 (m, 1 H), 4.12 (m, 1 H), 3.98 (m, 1 H), 3.12 (s, 3H), 2.94 (s,3H), 2.83 (m, 2H), 2.42 (m, 1 H), 1 .89 (m, 2H), 1.04 (m, 3H)„0.59 (m, 1 H). LCMS (m/z, ES⁺)= 577 (M+H).

Example 68

5-cvclopropyl-6-(N-(2-(4-fluoro-1 -hydroxy- 1 ,3-dihvdrobenzorclH ,21oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: 1-(2-bromo-6-fluorophenyl)prop-2-en-1-ol

To a solution of 2-bromo-6-fluorobenzaldehyde (5 g, 24.6 mmol) in dry THF (100 mL) was added vinylmagnesium bromide (27.1 mL, 27.1 mmol, 1 M/L) drop wise at -40 °C. After stirring for 30 min at this temperature, the reaction mixture was warmed to room temperature and poured into ice/water (150 mL). The aqueous layers were extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄. After the removal of solvent, it afforded 1-(2-bromo-6-fluorophenyl)prop-2-en-1 -ol (5.2 g, 22.5 mmol, 94 % crude yield) as a light-yellow oil. LCMS {m/z, ES⁺)= 232 (M+H)

Step 2: (1-(2-bromo-6-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane

To a solution of 1-(2-bromo-6-fluorophenyl)prop-2-en-1 -ol (5.2 g, 22.5 mmol) in DCM (100 mL) were added TBSCI (3.7 g, 24.7 mmol) and imidazole (2.3 g, 33.7 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred at rt for 2 h. The reaction mixture was poured into water (150 mL). The aqueous layer was extracted with DCM (3 x 100 mL) and the combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, it afforded (1-(2-bromo-6-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane (6.5 g 18.8 mmol, 84 % crude product) as a yellow oil. LCMS {m/z, ES⁺)= 346 (M+H) Step 3: 3-(2-bromo-6-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol

To a solution of (1 -(2-bromo-6-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane (6.5 g 18.8 mmol) in THF (1 18 mL) was added 9-BBN (4.64 g, 20.7 mmol) at room temperature and the reaction solution was stirred at rt for 4 h. After the reaction solution was cooled to 0 °C, NaOH (54 mL, 3 N/L) and H₂0₂ (54 mL, 30 %) were added drop wise and stirred at rt for 2 h. The reaction mixture was quenched with aq. Na₂S₂0₄ and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H₂0 (3 x 100 mL). After the removal of solvent, it afforded 3-(2-bromo-6-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1 -ol (6.2 g, 17.1 mmol, 91 % yield) as a colorless liquid. Step 4: (3-bromo-1-(2-bromo-6-fluorophenyl)propoxy)(tert-butyl)dimethylsilane

111 To a solution of 3-(2-bromo-6-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol (6.2 g, 17.1 mmol) and NBS (6.09 g, 34.2 mmol) in DCM (100 ml.) was added PPh₃ (8.9 g, 34.2 mmol) drop wise in DCM (10 ml.) under nitrogen and stirred at room temperature for 2 hours. The reaction mixture was poured into ice/water (100 ml.) and extracted with DCM (100 ml_). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford (3- bromo-1 -(2-bromo-6-fluorophenyl)propoxy)(tert-butyl)dimethylsilane (5.1 g, 12 mmol, 70 % yield) Step 5: 6-(N-(3-(2-bromo-6-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide

A solution of (3-bromo-1 -(2-bromo-6-fluorophenyl)propoxy)(tert-butyl)dimethylsilane (1 .26 g, 2.97 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (1 g, 2.48 mmol), K₂C0₃ (0.68 g, 4.96 mmol) and Kl (0.41 g, 2.48 mmol) in DMF (20 ml.) was heated at 80 °C for 2 hours under a nitrogen atmosphere. After cooling the mixture to room temperature, water was added and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(/V-(3-(2-bromo-6-fluorophenyl)- 3-(tert-butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methylbenzofuran-3-carboxamide (1 .5 g, 2 mmol, 82 % yield) as a white solid. LCMS {m/z, ES⁺)= 737 (M+H)

Step 6: 6-(N-(3-(2-bromo-6-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl- 2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 6-(N-(3-(2-bromo-6-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .5 g, 2.03 mmol) and HCI (5N aq., 15 ml_, 75 mmol) in THF (30 ml.) was stirred at 45 °C for 12 hours. The reaction mixture was diluted with water (50 mg) and EtOAc (150 ml_). The separated organic layer was dried over anhydrous Na₂S0₄. After the removal of solvent, it afforded 6-(/V-(3-(2-bromo-6-fluorophenyl)-3- hydroxypropyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3- carboxamid (1 .1 g, 1 .72 mmol, 85 % yield) as a light-yellow solid. Step 7: 5-cyclopropyl-6-(N-(2-(4-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide A solution of 6-(/V-(3-(2-bromo-6-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide (1 .1 g, 1.72 mmol), PdCI₂(dppf) (36 mg, 0.05 mmol), dppf (27 mg, 0.05 mmol), KOAc (237 mg, 1.72 mmol) and Pin₂B₂ (655 mg, 2.58 mmol) in dioxane (50 mL) was heated at 90 °C for 1 h under nitrogen atmosphere. The mixture was poured into ice/water (50 mL). The aqueous layers were extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with reverse phase HPLC to afford 5-cyclopropyl-6-(N-(2-(4-fluoro-1 -hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-3-yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (200 mg, 0.34 mmol, 20 % yield) as a white solid. ¹H NMR (300MHz, METHANOL-d4) δ: 7.94 (m, 2 H), 7.73 - 7.68 (d, 1 H), 7.43 - 7.32 (m, 2 H), 7.27 - 7.07 (m, 4 H), 5.48 - 5.40 (m, 1 H), 4.12 - 3.78 (m, 2 H), 3.14 (d, 3 H), 2.94 (s, 3 H), 2.46 - 2.35 (m, 2 H), 1.81 - 1.68 (m, 1 H), 1 .07 - 0.90 (m, 3 H), 0.69 - 0.57 (m, 1 H); LCMS (m/z ES⁺) = 581 (M+1 ).

Example 69

5-cvclopropyl-6-(N-(2-(5-fluoro-1 -hydroxy- 1 ,3-dihvdrobenzorclH ,21oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: 1-(2-bromo-5-fluorophenyl)prop-2-en-1-ol

To a solution of 2-bromo-5-fluorobenzaldehyde (5 g, 24.6 mmol) in dry THF (100 mL) was added vinylmagnesium bromide (27.1 mL, 27.1 mmol, 1 M) drop wise at -40 °C under a nitrogen atmosphere. The reaction mixture was stirred for 30 min at this temperature and then warmed to room temperature. The reaction mixture was poured into ice/water (150 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were washed with brine (50 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, it afforded 1-(2-bromo-5-fluorophenyl)prop-2-en-1 -ol (5.9 g, 25.5 mmol, 98 % crude yield) as a yellow oil. Step 2: (1-(2-bromo-5-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane

To a solution of 1-(2-bromo-5-fluorophenyl)prop-2-en-1 -ol (5.9 g, 25.5 mmol) in DCM (100 mL) were added TBSCI (4.2 g, 28.1 mmol) and imidazole (2.6 g, 38.2 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was poured into water (150 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0_4. Removal of the solvent under reduced pressure afforded (1-(2-bromo-5-fluorophenyl)allyloxy)(tert- butyl)dimethylsilane (6.2 g 18 mmol, 72 % crude yield) as a colorless liquid.

Step 3: 3-(2-bromo-5-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol

To a solution of (1 -(2-bromo-5-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane (6.2 g 18 mmol) in THF (100 mL) was added 9-BBN (4.2 g, 18.8 mmol) at room temperature. After stirring at room temperature for 4 hours, the reaction was cooled to 0 °C followed by the slow addition of NaOH (54 mL, 3 N/L) and H₂0₂ (54 mL, 30 %), and then stirring was maintained at room temperature for 2 more hours. The reaction mixture was quenched with aq. Na₂S₂0₄ and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H₂0 (3 x 100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography (PE: EA= 1 :10) to afford 3-(2-bromo-5- fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1 -ol (5 g, 13.8 mmol, 77 % yield) as a colorless oil.

Step 4: (3-bromo-1-(2-bromo-5-fluorophenyl)propoxy)(tert-butyl)dimethylsilane

To a solution of 3-(2-bromo-5-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol

(5 g, 13.8 mmol) and NBS (4.9 g, 27.6 mmol) in DCM (100 mL) was added PPh₃ (7.2 g, 27.6 mmol) drop wise in DCM (10 mL) under nitrogen atmosphere and stirred at room

temperature for 1 hour. The reaction solution was quenched with water (100 mL) and extracted with DCM (100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column

chromatography (PE: EA= 1 :100) to afford (3-bromo-1-(2-bromo-5- fluorophenyl)propoxy)(tert-butyl)dimethylsilane (5.2 g, 12.2 mmol, 89 % yield)

Step 5: 6-(N-(3-(2-bromo-5-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N^ methylbenzofuran-3-carboxamide

A solution of (3-bromo-1-(2-bromo-5-fluorophenyl)propoxy)(tert-butyl)dimethylsilane (1 .26 g, 2.97 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (1 g, 2.48 mmol), K₂C0₃ (0.68 g, 4.96 mmol) and Kl (0.41 g, 2.48 mmol) in DMF (50 mL) was heated at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into ice/water (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(3-(2-bromo-5-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .5 g, 2 mmol, 80 % yield). LCMS {m/z, ES⁺)= 737 (M+H)

Step 6: 6-(N-(3-(2-bromo-5-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl- 2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 6-(N-(3-(2-bromo-5-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .5 g, 2 mmol) and HCI (15 mL, 75 mmol, 5M) in THF (30 mL) was heated at 80 °C for 12 hours. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, it afforded 6-(/V-(3-(2-bromo-5-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)- 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamid (1 .1 g, 1 .75 mmol, 85 % yield) as a white solid.

Step 7: 5-cyclopropyl-6-(N-( 2-( 5-fluoro-1 -hydroxy- 1, 3-dihydrobenzo[c][ 1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-meth^

A solution of 6-(/V-(3-(2-bromo-5-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide (1 .1 g, 1.75 mmol), PdCI₂(dppf) (36.5 mg, 0.05 mmol), KOAc (724 mg, 5.25 mmol) and Pin₂B₂ (889 mg, 3.5 mmol) in dioxane (50 mL) was heated at 90 °C for 1 hour under nitrogen. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to afford 5-cyclopropyl-6-(/V-(2-(5-fluoro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-3-yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-/\/- methylbenzofuran-3-carboxamide (100 mg, 0.17 mmol, 12 % yield) as a yellow solid. ¹H NMR (300MHz, METHANOL-d4) δ: 7.94 - 7.89 (m, 2 H), 7.72 - 7.59 (m, 2 H), 7.27 - 6.94 (m, 5 H), 5.30 - 5.22 (m, 1 H), 4.1 1 - 3.82 (m, 2 H), 3.13 - 3.1 1 (d, 3 H), 2.94 (s, 1 H), 2.45 - 2.28 (m, 2 H), 1.82 - 1 .67 (m, 1 H), 1.07 - 0.92 (m, 3 H), 0.68 - 0.60 (m, 1 H). LCMS (m/z, ES⁺)= 581 (M+1 ).

Example 70

5-cvclopropyl-6-(N-(2-(6-fluoro-1 -hydroxy- 1 ,3-dihvdrobenzorclH ,21oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: 1-(2-bromo-4-fluorophenyl)prop-2-en-1-ol

To a solution of 2-bromo-4-fluorobenzaldehyde (10.2 g, 50 mmol) (Beihua) in dry THF (100 mL) was added vinylmagnesium bromide (50 mL, 50 mmol, 1 M) drop wise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 hour at this temperature and then warmed to room temperature for 1 hour. The reaction mixture was poured into NH₄CI (100 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were washed with water (200 mL), brine (200 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, it afforded 1 -(2-bromo-4-fluorophenyl)prop-2-en-1-ol (1 1.9 g, quantitative) as a yellow oil.

Step 2: (1-(2-bromo-4-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane

To a solution of 1-(2-bromo-4-fluorophenyl)prop-2-en-1 -ol (5.9 g, 25.5 mmol) in DCM (100 mL) were added TBSCI (9.33 g, 61 .8 mmol) and imidazole (7.00 g, 103 mmol) at 0 °C. The reaction mixture was warmed to room temperature and maintained with stirring for 2 hours. The reaction mixture was poured into water (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layers were dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with column chromatography to afforded (1 -(2- bromo-4-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane (14.45 g, 82 % yield) as a colorless liquid.

Step 3: 3-(2-bromo-4-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol

To a solution of (1 -(2-bromo-4-fluorophenyl)allyloxy)(tert-butyl)dimethylsilane (6.9 g 20 mmol) in THF (100 mL) was added 9-BBN (2.93 g, 12 mmol) at room temperature. After stirring at room temperature for 7 hours, the reaction was cooled to 0 °C followed by the slow addition of NaOH (90 mL, 1 N/L) and H₂0₂ (230 mL, 30 %) and then stirred at room temperature for 2 hours. The reaction mixture was quenched with aq. Na₂S₂0₄ and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H₂0 (3 x 100 mL) and brine (100 mL) and then dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 3-(2-bromo-4- fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1 -ol (4.4 g, 60 % yield) as a colorless oil. Step 4: (3-bromo-1-(2-bromo-4-fluorophenyl)propoxy)(tert-butyl)dimethylsilane

To a solution of 3-(2-bromo-4-fluorophenyl)-3-(tert-butyldimethylsilyloxy)propan-1-ol (4.4 g, 12.1 mmol) and NBS (4.3 g, 24.2 mmol) in DCM (50 mL) was added drop wise PPh₃ (6.3 g, 24.2 mmol) in DCM (20 mL) under nitrogen atmosphere and stirred at room temperature for 20 minutes. The reaction solution was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column

chromatography to afford (3-bromo-1-(2-bromo-4-fluorophenyl)propoxy)(tert- butyl)dimethylsilane (3.3 g, 64 % yield) as a colorless oil.

Step 5: 6-(N-(3-(2-bromo-4-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide

A solution of (3-bromo-1-(2-bromo-4-fluorophenyl)propoxy)(tert-butyl)dimethylsilane

(1.28 g, 3 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (1 g, 2.5 mmol), K₂C0₃ (1.03 g, 7.5 mmol) and Kl (0.415 g, 2.5 mmol) in DMF (50 mL) was heated at 80 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into ice/water (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(3-(2-bromo-4-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .72 g, 92 % yield). LCMS {m/z, ES⁺)= 747.0 (M+H).

Step 6: 6-(N-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl- 2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of 6-(N-(3-(2-bromo-4-fluorophenyl)-3-(tert- butyldimethylsilyloxy)propyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .5 g, 2 mmol) in THF (15 mL) was added drop wise aq. HCI (5N, 15 mL, 75 mmol) at room temperature and then heated at 80 °C for 15 hours. The reaction mixture was cooled to room temperature and extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo to give 6-(N-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5-cyclopropyl-2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .1 g, 85 %) as a white solid. Step 7: 5-cyclopropyl-6-(N-( 2-( 6-fluoro-1 -hydroxy- 1, 3-dihydrobenzo[c][ 1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 6-(N-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .1 g, 1.72 mmol), PdCI₂(dppf) (36.5 mg, 0.05 mmol), KOAc (724 mg, 5.25 mmol) and Pin₂B₂ (889 mg, 3.5 mmol) in dioxane (50 mL) was degassed and refilled with nitrogen three times and then heated at 90°C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by pre-HPLC to afford 5- cyclopropyl-6-(N-(2-(6-fluoro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (180 mg, 21 %) as a yellow solid. ¹H NMR (300MHz, METHANOL-^) δ= 7.94 - 7.89 (m, 2 H), 7.72 - 7.59 (m, 2 H), 7.27 - 6.94 (m, 5 H), 5.30 - 5.22 (m, 1 H), 4.1 1 - 3.82 (m, 2 H), 3.13 - 3.1 1 (d, 3 H), 2.94 (s, 1 H), 2.45 - 2.28 (m, 2 H), 1 .82 - 1 .67 (m, 1 H), 1 .07 - 0.92 (m, 3 H) , 0.68 - 0.60 (m, 1 H). LCMS (m/z, ES⁺)= 581 (M+H).

Example 71

5-cvclopropyl-2-(4-fluorophenyl)-6-r{r(4R)-2-hvdroxy-1 ,2-oxaborolan-4- yllmethyl}(methylsulfonyl)aminol-N-methyl-1 -benzofuran-3-carboxamide: Alternate Synthetic

Protocol for Example 8

Stage 1 : (4R, 5S)-4-methyl-5-phenyl-3-[3-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2- yl)propanoyl]- 1, 3-oxazolidin-2-one

A suspension of sodium tert-butoxide (0.419 g, 4.36 mmol), DPEPhos (0.783 g, 1.453 mmol), and copper(l) chloride (0.144 g, 1.453 mmol) in THF (50 mL) was stirred at room temperature, cooled to 0°C, and treated drop wise with bis(pinacolato)diboron (12.91 g, 50.9 mmol) (in 50 mL THF). Stirring was maintained for 45 minutes and then (4R,5S)-3-acryloyl- 4-methyl-5-phenyl-1 ,3-oxazolidin-2-one (1 1 .2 g, 48.4 mmol) (in THF, 50 mL) was added drop wise and the solution was warmed to room temperature and maintained with stirring for 3 hours. The mixture was passed through glass filter paper, diluted with celite, concentrated, and purified by column chromatography to afford (4R,5S)-4-methyl-5-phenyl-3-[3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)propanoyl]-1 ,3-oxazolidin-2-one (8.13 g, 22.63 mmol, 47 % yield) as a white solid. ¹H NMR (METHANOL-d₄) d: 7.30 - 7.47 (m, 5H), 5.78 (d, J = 7.4 Hz, 1 H), 4.77 (t, J = 6.9 Hz, 1 H), 2.88 - 3.14 (m, 2H), 1.16 - 1.30 (m, 12H), 0.95 (q, J = 6.5 Hz, 2H), 0.83 (d, J = 6.6 Hz, 3H)

Stage 2: (2R)-3-[(phenylmethyl)oxy]-2-[(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)methyl]- 1-propanol

A solution of (4R,5S)-4-methyl-5-phenyl-3-[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)propanoyl]-1 ,3-oxazolidin-2-one (5.0 g, 13.92 mmol) in DCM (69.6 ml) was cooled to 0°C and then treated with 1 M TiCI₄ in DCM (16.70 ml, 16.70 mmol). The yellow reaction was stirred for 10 minutes, then DIEA (3.04 ml, 17.40 mmol) was added to the reaction. After stirring at 0°C, the reddish reaction was treated with chloromethyl phenylmethyl ether (2.508 ml, 18.09 mmol). The mixture was slowly allowed to warm to room temperature with stirring for 2 hours. The reaction treated with DCM, saturated aqueous ammonium chloride, and water. The layers were separated and the combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated. The crude residue is dissolved in THF (41.5 ml) and MeOH (0.403 ml, 9.96 mmol) and placed under a nitrogen atmosphere and cooled to 0°C. The solution was treated with 2M in THF LiBH₄ (4.98 ml, 9.96 mmol). After stirring at room temperature overnight, the reaction was quenched by the addition of MeOH and saturated aqueous ammonium chloride and extracted with EtOAc The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated. The crude residue purified by column

chromatography (40g) eluting with 0-30% EtOAc/Hexanes. To afford (2R)-3- [(phenylmethyl)oxy]-2-[(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl]-1 -propanol as a clear oil. ¹ H NMR (METHANOL-d₄) d: 7.22 - 7.38 (m, 5H), 4.48 (s, 2H), 3.51 - 3.59 (m, 1 H), 3.41 - 3.51 (m, 2H), 3.33 - 3.41 (m, 1 H), 3.26 - 3.33 (m, 1 H), 2.02 - 2.1 1 (m, 1 H), 1.20 (d, J = 2.9 Hz, 12H), 0.75 (dd, J = 7.2, 2.9 Hz, 2H)

Stage 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-((methylsulfonyl){(2R)-3- [(phenylmethyl)oxy]-2-[(4,4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)methyl]propyl}amino)- 1- benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (175 mg, 0.435 mmol), (2R)-3-[(phenylmethyl)oxy]-2-[(4,4,5,5- tetramethyl-1 , 3, 2-dioxaborolan-2-yl)methyl]-1 -propanol (233 mg, 0.761 mmol), and triphenylphosphine (257 mg, 0.978 mmol) in tetrahydrofuran (5 ml.) was maintained at 0°C with stirring and treated drop wise with DIAD (0.169 ml_, 0.870 mmol). The mixture was warmed to room temperature, maintained with stirring for 16 hours, diluted with celite, concentrated, and the residue absorbed on celite and purified by column chromatography (20 to 50% EtOAc/hexanes) to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- ((methylsulfonylX(2R)-3-[(phenylmethyl)oxy]-2-[(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)methyl]propyl}amino)-1-benzofuran-3-carboxamide (235 mg, 0.340 mmol, 78 % yield) as a white foam with NMR/LCMS properties identical to material described in Example 8. Stage 4: 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[(4R)-2-hydroxy-1,2-oxaborolan-4- yl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-((methylsulfonyl){3- [(phenylmethyl)oxy]-2-[(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methyl]propyl}amino)-1- benzofuran-3-carboxamide (.600 g, 0.869 mmol) and 10% Pd/C (Degussa Type (wet). (300 mg, 0.869 mmol) in tetrahydrofuran (10 mL) was maintained under 40 psi hydrogen gas with rapid stirring for 16 hours. The mixture was filtered through celite, concentrated under reduced pressure, dissolved in tetrahydrofuran (10 ml_)/5.0N HCI (aq) (1 .216 mL, 6.08 mmol), and PS-benzene boronic acid (2.6 mmol/g) (1 .668 g, 4.34 mmol) was added. The mixture was maintained with stirring at room temperature for 2 hours, filtered through celite, concentrated, and partitioned between dichloromethane and HCI (pH < 3). The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[(4R)-2- hydroxy-1 ,2-oxaborolan-4-yl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3- carboxamide (297 mg, 0.594 mmol, 68.3 % yield) as a white foam with > 95% purity and > 95% ee% as determined by chiral chromatography. NMR spectroscopic properties and retention time using chiral hplc are identical to those described for the early eluting enantiomer from Example 8. The residue was dissolved in acetonitrile/water, frozen, and stored on a lyophilizer for 16 hours to give a free-flowing white solid.

Absolute configuration was assigned as 4R based on VCD spectroscopy; Theory Level: ONIOM method, b3pw 91/6-31 1 +g (2df) applied to S0₂ with B3LYP/6-31 1 G(d,p) applied to the rest of the molecule. Assignment consistent with sense of diastereoinduction anticipated from Aldol Step #1.

Example 72

2-(4-chlorophenyl)-5-cvclopropyl-6-rr2-(6-fluoro-1 -hvdroxy-1 ,3-dihvdro-2,1 -benzoxaborol-3- yl)ethyll(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

One can prepare 2-(4-chlorophenyl)-5-cyclopropyl-6-[[2-(6-fluoro-1-hydroxy-1 ,3- dihydro-2, 1-benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-/\/-methyl-1-benzofuran-3- carboxamide in direct analogy to the preparation described in Example 69 by substituting 5- cyclopropyl-2-(4-chlorophenyl)- A/-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3- carboxamide (synthesis described in example 34) for 5-cyclopropyl-2-(4-fluorophenyl)- N- methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide.

Example 73

2-(4-chlorophenyl)-5-cvclopropyl-6-[[2-(1 -hvdroxy-1 ,3-dihydro-2, 1-benzoxaborol-3- l)ethyll(methylsulfonyl)aminol-/\/-methyl-1 -benzofuran-3-carboxamide

One can prepare 2-(4-chlorophenyl)-5-cyclopropyl-6-[[2-(1-hydroxy-1 ,3-dihydro-2,1 - benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide in direct analogy to the preparation described in Example 69 by substituting 5-cyclopropyl-2-(4- chlorophenyl)- A/-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (synthesis described in example 34) for 5-cyclopropyl-2-(4-fluorophenyl)- /V-methyl-6- [(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide. Example 74

6-rr2-(6-chloro-1-hvdroxy-1 ,3-dihvdro-2, 1-benzoxaborol-3-yl)ethyll(methylsulfonyl)aminol-2- -chlorophenyl)-5-cvclopropyl-/\/-methyl-1-benzofuran-3-carboxamide

One can prepare 6-[[2-(6-chloro-1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-3- yl)ethyl](methylsulfonyl)amino]-2-(4-chlorophenyl)-5-cyclopropyl-/\/-methyl-1-benzofuran-3- carboxamide in direct analogy to the preparation described in Example 69 by substituting 5- cyclopropyl-2-(4-chlorophenyl)- A/-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3- carboxamide (synthesis described in example 34) for 5-cyclopropyl-2-(4-fluorophenyl)- N- methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide.

BIOLOGICAL ASSAYS

Replicon Luciferase cell based assay

Method

150μΙ_ of a 1 mM stock solution in DMSO of each test compound was transferred into in the first column of a 96 well, V-bottom microplate, to give 200 times the top concentration of the required dilution series. Aliquots of 50μΙ_ were added to each well of the remaining rows containing 100μΙ_ of DMSO giving a 1 :3 dilution series over ten points. Columns 1 1 and 12 contained DMSO only for the positive and negative control, respectively. 10μΙ_ of each well were transferred into 90μΙ_ of DMEM medium (Invitrogen #41965-039) supplemented with 5% v/v foetal calf serum, 1 % v/v non-essential amino acids solution, 100 units/ml penicillin, 100μg/ml streptomycin and 2mM L-glutamine to give 20 times the top

concentration of the required dilution series.

For replicon assays, Huh-7 cells stably transfected with sub-genomic HCV NS3-

NS5B replicons of either genotype 1 b (the ET subline described by Pietschmann,T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. & Bartenschlager, R., Journal of Virology, 2002, 76, 4008-4021 ), genotype 1 a (subline 1.19 constructed in-house) or genotype 1 b C316N (constructed in-house) linked to a firefly luciferase reporter gene were used. Monolayers nearing confluency were stripped from growth flasks with versene-trypsin solution and the cells re-suspended in assay medium comprising DMEM. Alternatively, frozen cell stocks were prepared and validated to function comparably to fresh cells. Frozen cells were thawed rapidly from a liquid Nitrogen tank in a 37°C waterbath and transferred to a large conical tube where complete media was added dropwise. Cells were centrifuged for 5 mintues at 1 K rpm and resuspended in complete medium. Trypsinized cells or resuspended frozen cells were counted and diluted to the approporiate concentration for assay purposes. 95μΙ_ of suspension containing either 15,000 cells (genotype 1 b luciferase replicon) or 20,000 cells (genotype 1 a luciferase replicon) were added to all wells of a 96 well plate (Perkin Elmer, #6005686), except medium controls in column 12 of the assay plate. The cell suspension was dosed with 5μΙ_ of compound solution and the plate was incubated for 48 hours at 37°C in a 5% C0₂ atmosphere. For toxicity the cells in one plated were treated with Cell Titer Glo (Promega, #G7573). A solution of Cell Titer Glo was prepared according to the manufacturer's instructions, and 100 μΙ_ added to each well. The plate was then read for luminescence on an Envision.

For potency a solution of Steady Glo (Promega, #E2550) was prepared according to the manufacturer's instructions and 100μΙ_ added to each well. After a 20 minute incubation the plate was then read for luminescence on an Envision.

Data Analysis

Toxicity : The luminescence values from duplicate wells were averaged and expressed as a percentage of the mean absorbance of compound free control wells to determine comparative cell viability. Compound cytotoxicity was expressed either as the lowest concentration at which a significant reduction in viability was observed or a 50% toxic concentration (CCID₅₀) was determined by plotting percentage cytotoxicity against compound concentration using ActivityBase (IDBS Software) with curve fitting done through the XC50 module.

Potency: The luminescence values from all compound-free wells containing cells were averaged to obtain a positive control value. The mean luminescence value from the compound-free wells that had received no cells was used to provide the negative

(background) control value. The background value was subtracted from the readings from the wells at each compound concentration and all values were expressed as a percentage of the positive control signal. The quantifiable and specific reduction of luciferase signal in the presence of a drug is a direct measure of replicon inhibition. BioAssay Enterprise

(CamebridgeSoft) with the XC50 module for curve fitting was used to plot the curve of percentage inhibition against compound concentration and derive the 50% inhibitory concentration (IC₅₀) for the compound. The EC50 values obtained from duplicate plates were averaged. Results are expressed in Table 1.

Most of the compounds tested demonstrated activity against NS5B-316N that was equal to, or close to the wildtype NS5B-316C. NS5B-316N is a polymorphic change on residue 316 that occurs in about 40% of HCV genotype 1 b patients and it is therefore advantageous for a compound to exhibit activity against NS5B-316N.

Table 1

4 _{** *** **}

5 _** _*** _*

6 _*** _*** _*

7 _*** _*** _***

8 _*** _*** _***

9 _*** _*** _**

10 _*** _*** _***

1 1 _** _** _**

12 _*** _*** _***

13 _* _** ND

14 _** _*** _**

15 _** _** _*

16 _** _** _**

17 _*** _*** _**

18 _*** _*** _***

19 _** _*** _**

20 _*** _*** _**

21 _** _*** _**

22 _** _*** _**

23 _*** _*** _**

24 _* _** >1500

25 _* _* >1500

26 _* _* >1500

27 _*** _*** _**

28 _** _*** _**

29 _** _*** _**

30 _** _*** _**

31 _** _** _*

32 _** _** _**

33 _** _*** _**

34 _*** _*** _***

35 _** _*** _**

36 _** _*** _**

37 _*** _*** _**

38 _*** _*** _** 39 _{** *** *}

40 _** _*** _**

41 _*** _*** _**

42 _*** _*** _**

43 _*** _*** _**

44 _*** _*** _***

45 _*** _*** _**

46 _** _** _*

47 _** _*** _**

48 _** _*** _**

49 _*** _*** _**

50 _** _*** _**

51 _** _*** _**

52 _*** _*** _***

53 _*** _*** _***

54 _** _*** _**

55 _*** _*** _**

56 _* _** _*

57 _** _*** ND

58 _*** _*** _***

59 _** _*** _**

60 _** _*** _**

61 _*** _*** _**

62 _* _** _**

63 _*** _*** _**

64 _** _*** _**

65 _** _*** _**

66 _** _** _**

67 _*** _*** _**

68 _** _*** _**

69 _*** _*** _**

70 _*** _*** _**

^* 100 - 1500 nM

*^* 10 - 100 nM

*^** <10 nM

ND = not determined

Claims

1. A compound of formula (I):

(I)

wherein:

R¹ is one or more substituents independently selected from the group consisting of halogen, Ci_-6alkyl, alkoxy, -CN, -CF₃ and OR¹⁰ wherein R¹⁰ is aryl optionally substituted with halogen;

_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy;

-S(0)₂R³, -C(0)0R³, or -C(0)NR 6°_DR7

R is Ci_-6alkyl or C_3-6cycloalkyl;

R⁶ is hydrogen;

R⁷ is hydrogen or C_1-6alkyl;

X is Ci_-6alkylene optionally substituted with Ci_-6alkyl, hydroxy, amino or C_3-6cycloalkyl;

R is

(a) Het optionally substituted with one or more substituents selected from the group consisting of C_1-6alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF₃ and -OCF₃;

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^D);

R⁹ is alkylene optionally substituted by Ci_-6alkyl; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) according to claim 1 wherein:

R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy;

R⁴ is -S(0)₂R⁵, -C(0)OR⁵, or -C(0)NR⁶R⁷ _;

R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

R⁶ is hydrogen;

R⁷ is hydrogen or C_1-6alkyl;

(a) Het optionally substituted with one or more substituents selected from the group consisting of C_1-6alkyl and hydroxy;

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^b);

R^a and R^b are hydrogen;

R⁹ is alkylene optionally substituted by C_1-6alkyl; or a pharmaceutically acceptable salt thereof.

3. A compound of formula (I) according to claim 1 wherein:

R² is C_1-6alkyl optionally substituted with hydroxy;

R³ is C_3-6cycloalkyl;

R⁴ is -S(0)₂R⁵ R⁵ is Ci_-6alkyl;

X is Ci_-6alkylene optionally substituted with Ci_-6alkyl;

R is

(a) Het optionally substituted with one or more substituents selected from the group consisting of Ci_-6alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF₃ and -OCF₃; or

(b) OR⁹B(OR^a)(OR^b);

R^a and R^b are hydrogen;

4. A compound of formula (I) according to any of claims 1 - 3 wherein R¹ is one or two substituents selected from halogen.

5. A compound of formula (I) according to any of claims 1 - 4 wherein R² is Ci_-6alkyl.

6. A compound of formula (I) according to any of claims 1 - 5 wherein R³ is C₃-₆cycloalkyl.

7. A compound of formula (I) according to any of claims 1 , 2, 4, 5, or 6 wherein R⁴ is -

S(0)₂R⁵.

8. A compound of formula (I) according to any of claims 1 to 7 wherein X is C_1-6alkylene.

9. A compound of formula (la)

(la) wherein:

R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy; R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

X is Ci_-6alkylene optionally substituted with Ci_-6alkyl, hydroxy, amino or C_3-6cycloalkyl; (a) Het optionally substituted with one or more substituents selected from the group consisting of Ci_-6alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF₃ and -OCF₃;

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^b);

10. A compound of formula (la) according to claim 9 wherein: R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy;

R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

X is C_1-6alkylene optionally substituted with C_1-6alkyl. hydroxy, amino or C_3-6cycloalkyl; R⁸ is

(b) OR⁹B(OR^a)(OR^b); or

(c) N(R⁵)R⁹B(OR^a)(OR^b);

R^a and R^b are hydrogen;

1 1 . A compound of formula (I) or (la) according to any of claims 1 - 10 wherein R⁸ is Het optionally substituted with one or more substituents selected from the group consisting of C-i. ₆alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, CF₃ and OCF₃;

12. A compound of formula (la) according to any of claims 9 - 1 1 wherein R³ is C_3- ₆cycloalkyl.

13. A compound according to any of claims 1 - 1 1 wherein R⁸ is Het optionally substituted with one or more substituents selected from the group consisting of Ci_-6alkyl and hydroxyl;

14. A compound according to any of claims 1 - 10 wherein R⁸ is OR⁹B(OR^a)(OR^b).

15. A compound according to any of claims 1 - 10 wherein R⁸ is N(R⁵)R⁹B(OR^a)(OR^b).

16. A compound selected from the group consisting of:

[({2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1-methylethyl)oxy]-1 -benzofuran-6- yl}(methylsulfonyl)amino]ethyl}oxy)methyl]boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-6- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-4- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

{3-[{2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1 -benzofuran-6- yl}(methylsulfonyl)amino]ethyl}(methyl)amino]propyl}boronic acid; 5-ethyl-2-(4-Fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4-yl)methyl](methylsulfonyl)ami /V-methyl-1-benzofuran-3-carboxamide;

2-(4-Fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]-/\/- methyl-5-(1 -methylethyl)-1 -benzofuran-3-carboxamide;

2-(4-Fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborolan-4-yl)methyl](methylsulfonyl)amino]-/\/,5- dimethyl-1-benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1 ,2-oxaborinan-5-yl)methyl]

(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[2-(2-hydroxy-1 ,2-oxaborolan-5- yl)ethyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

[({(2R)-3-[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]-2-methylpropyl}oxy)methyl]boronic acid;

[({(2S)-3-[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]-2-methylpropyl}oxy)methyl]boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)propan-2- ylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-6-(N-((2-hydroxy-1 ,2-oxaborolan-4-yl)methyl)methylsulfonamido)-N-methyl-2- (4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide;

2-(4-Chlorophenyl)-5-cyclopropyl-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide; 5-Cyclopropyl-2-(3-fluorophenyl)-6-(N-((2-hydroxy-1 ,2-oxaborolan-4- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(3-fluorophenyl)-6-(N-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

2-(4-Chlorophenyl)-5-cyclopropyl-6-(/\/-((1 -hydroxy-1 , 3-dihydrobenzo[c][i,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(3,4-difluorophenyl)-6-(N-((1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide;

(±)-5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1 -hydroxy-3-methyl-1 ,3-dihydro-2, 1 -benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-6-(N-((7-fluoro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[(3S)-1-hydroxy-3-methyl-1 ,3-dihydro-2, 1-benzoxaborol-

5-yl]methyl}(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[(3R)-1-hydroxy-3-methyl-1 ,3-dihydro-2,1 -benzoxaborol-

5-yl]methyl}(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(1 -(1 -hydroxy-1 ,3-dihydrobenzo[c][i,2]oxaborol-5- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1 -hydroxy-1 , 3-dihydrobenzo[c][i, 2]oxaborol-5- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide;

Methyl 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-1 -hydroxy-1 , 3-dihydro-2, 1 -benzoxaborole-7-carboxylate;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[1 -hydroxy-7-(hydroxymethyl)-1 ,3-dihydro-2, 1- benzoxaborol-5-yl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide; 6-(/V-((7-Chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][7,2]oxab

5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-3,4-dihydro-1 /-/-2, 1-benzoxaborin-6- yl)methyl](methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-/\/-ethyl-6-[[(7-fluoro-1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-((1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)methyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-((1-hydroxy-7-(trifluoromethyl)-1 ,3- dihydrobenzo[c][i,2]oxaborol-5-yl)methyl)methylsulfonamido)-/\/-methylbenzofuran-3- carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3S)-1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-3- yl]ethyl}(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3R)-1-hydroxy-1 ,3-dihydro-2, 1 -benzoxaborol-3- yl]ethyl}(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5- Cyclopropyl-2-(4-fluorophenyl)-6-[({1-hydroxy-7-[(trifluoromethyl)oxy]-1 ,3-dihydro-2,1 - benzoxaborol-5-yl}methyl)(methylsulfonyl)amino]-/V-methyl-1 -benzofuran-3-carboxamide;

6- (N-(2-(7-Chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3-yl)ethyl)methylsulfonamido)- 5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-6-[[(7-fluoro-1 -hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)methyl](methylsulfonyl)amino]-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide;

5- Cyclopropyl-6-(/V-(2-(7-fluoro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

6- [[2-(6-Chloro-1-hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide;

6-[[2-(5-Chloro-1-hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide;

6-[[2-(4-Chloro-1-hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-3-yl)ethyl](methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(/\/-(2-(1-hydroxy-3,4-dihydro-1 H-benzo[c][1 ,2]oxaborinin- 3-yl)ethyl)methylsulfonamido)-/\/-methylbenzofuran-3-carboxamide;

5-Cyclopropyl-6-(N-(2-(5-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide; 5-Cyclopropyl-6-(N-(2-(6-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxami

pharmaceutically acceptable salts thereof.

17. A compound selected from the group consisting of:

5- cyclopropyl-6-(N-((7-fluoro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

6- (/V-((7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][i,2]oxaborol-5-yl)methyl)methylsulfonamido)- 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3S)-1 -hydroxy-1 , 3-dihydro-2, 1 -benzoxaborol-3- yl]ethyl}(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-cyclopropyl-6-(N-(2-(6-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-3- yl)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide; and pharmaceutically acceptable salts thereof.

18. A compound selected from the group consisting of:

pharmaceutically acceptable salts thereof.

19. [({2-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino] ethyl}oxy)methyl]boronic acid or a pharmaceutically acceptable salt thereof.

20. A pharmaceutically acceptable salt of a compound as claimed in any of claims 1 to 19.

21. A pharmaceutical composition comprising a compound according to any of claims 1 to 19 together with at least one pharmaceutically acceptable excipient.

22. A compound of formula (I) or (I)' as claimed in any of claims 1 to 19 for use in therapy.

23. Use of a compound of formula (I) or (I)' as claimed in any of claims 1 - 19 in the manufacture of a medicament for treating or preventing a viral infection or disease associated with such infection.

24. Use according to claim 23 wherein the viral infection is HCV infection.

25. A compound of formula (I) or (la) as claimed in any of claims 1 to 19 for use in treating or preventing a viral infection or disease associated with such infection.

26. A compound of formula (I) or (la) according to claim 25 wherein the viral infection is HCV infection.

27. A method of treating or preventing a viral infection or disease associated with such infection comprising administering to a human a therapeutically effective amount of compound of formula (I) or (la) as claimed in any one of claims 1 to 19.

28. A method according to claim 27 wherein the viral infection is HCV infection.

29. A compound of formula (I) or (la) as claimed in any one of claims 1 to 19 in combination with one or more active anti-viral agents.